Generality
Thrombocytopenic thrombotic purpura ( TTP ) or Moschowitz syndrome is a rare blood disorder.
From the clinical point of view, this condition is associated with thrombotic microangiopathy, a disorder characterized by the pathological formation of platelet aggregates ( thrombi ), in the small blood vessels of the whole organism.
In thrombotic thrombocytopenic purpura, this results in:
- Reduction of platelets due to their excessive consumption (which is why it is called " thrombocytopenic" : these cells are used for blood coagulation);
- Mechanical damage to erythrocytes ( haemolytic anemia );
- Neurological symptoms .
The presentation is often acute and very serious : if the TTP is not recognized and treated, the episode can degenerate up to the coma and lead to death in 90% of cases .
The treatment of choice for thrombotic thrombocytopenic purpura is plasma exchange (ie the replacement of the patient's plasma with that from donors, but sometimes it is necessary to consider an immunosuppressive therapy or other interventions.
What's this
Thrombotic thrombocytopenic purpura: definition and characteristics
Thrombotic thrombocytopenic purpura is a haematological disease characterized by reduced platelets, haemolytic anemia and neurological disorders, alterations in renal function and fever.
The thrombocytopenia is caused by the reduced enzyme activity of ADAMTS 13 . This deficiency may be secondary to mutations in the gene encoding the protein ( hereditary form ) or it may be acquired during life, generally due to the body's own production of antibodies that go against this protein ( auto-immune form ) .
In any case, the consequence of this dysfunction is the formation of thrombus in the small blood vessels of the whole organism (which is why it is called thrombotic ).
In the course of life, episodes of thrombotic thrombocytopenic purpura can be single or repeated .
TTP: terminology and synonyms
Thrombotic thrombocytopenic purpura is also known as Moschowitz syndrome, from the name of the doctor who first described the clinical picture in 1924. However, the pathogenesis of TTP remained unrecognized until the 1980s.
Thrombotic microangiopathies: what they are
Thrombocytopenic thrombotic purpura (TTP) can be considered the "prototype" of thrombotic microangiopathies (MT), that is, occlusive disorders of the vascular microcirculation, characterized by systemic and / or intra-renal platelet aggregation (thrombi), from which they follow:
- Consuming platelet count ;
- Hemolytic anemia due to mechanical damage to erythrocytes.
The pathological formation of platelet aggregates (thrombi) does not cause the complete occlusion of the blood vessel, but the obstruction of the lumen, causing a dangerous decrease in the supply of oxygen to different organs (kidneys, liver, heart, brain, etc.) and a series of ischemia.
Causes
Thrombocytopenic thrombotic purpura is a multifactorial disease, that is, it depends on the combination of several contributing factors. TTP occurs mainly in adulthood .
In the pathogenesis of thrombotic thrombocytopenic purpura, von Willebrand factor (VWF or factor VIII) is implicated, very important in blood coagulation .
At the origin of the disease there would be a systemic endothelial damage, which results in the release of large amounts of VWF multimers, larger than those normally present at the plasma level, which interact with platelets (in practice, the von Willebrand factor accumulates and acts as an aggregation center for thrombocytes).
At this point, under normal conditions, a specific metal-protease intervenes, ADAMTS 13, which - as a cleavage enzyme - degrades high molecular weight multimers into monomers. In most patients with thrombocytopenic, acquired or familial thrombotic purpura, the activity of this plasma protein is reduced to less than 5% .
The consequence of ADAMTS 13 deficiency is the persistence of multimers produced by endothelial cells, which are not cleaved, predisposing adhesion and aggregation of platelets on their surface. The end result is the formation of microvascular thrombi with altered circulation and multi-organ ischemia. The complications of this cascade of events are potentially lethal.
Classification
Thrombocytopenic thrombotic purpura can be classified into:
- Familial form : it occurs after birth or in infancy, with very low values of platelets. In the plasma of patients with familial TTP, the activity of ADAMTS 13 is practically absent due to the homozygous mutation in the gene, located on chromosome 9q34, which codes for the enzyme. The inherited form of thrombotic thrombocytopenic purpura is transmitted in an autosomal recessive manner: the parents are healthy carriers of the mutation, while each child of the couple has a 25% chance of being sick.
- Acquired form : occurs during adolescence or adulthood, with very variable symptoms. In the acute phases of acquired thrombocytopenic thrombotic purpura, the ADAMTS 13 plasma activity is practically absent due to the presence (in 48-80% of cases) of auto-antibodies that inhibit the enzyme. At other times, there appears to be a transient defect in the production or reduced survival of ADAMTS 13.
Thrombocytopenic thrombotic purpura can be idiopathic also called "without a known cause"; this type of TTP represents a significant portion of the cases.
Another form of thrombotic thrombocytopenic purpura, on the other hand, is drug-mediated.
Aggravating and / or predisposing factors
Thrombotic thrombocytopenic purpura can occur in association with:
- Pregnancy and puerperium;
- Autoimmune diseases;
- Liver disease;
- Disseminated neoplasia;
- Inflammations or chronic metabolic pathologies;
- Infections;
- Sepsis;
- Medication (including ticlopidine, clopidogrel, quinidine, cyclosporin A and mitomycin C);
- Allogeneic stem cell transplantation;
- Solid organ transplantation;
- Major surgery.
Symptoms and Complications
Thrombocytopenic thrombotic purpura is characterized by microangiopathic hemolytic anemia, thrombocytopenia, involvement of the central nervous system, fever and renal failure . However, not always all these manifestations are present at the onset of the disease.
Furthermore, it should be remembered that extrinsic signs and symptoms of thrombotic thrombocytopenic purpura go hand in hand with the progressive formation of microthrombi in various organs and tissues, from which their functional damage results.
Uremic-hemolytic Gasser syndrome vs thrombotic thrombocytopenic purpura
When renal involvement represents the predominant trait at presentation of the clinical picture, the condition is defined as Gasser uremic-hemolytic syndrome (HUS) . However, the distinction between TTP and HUS is not always easy, so much so that some sources have proposed to interpret these two disorders as two manifestations of a single clinical entity.
Regarding the presentation, thrombotic thrombocytopenic purpura can be divided into two types:
- Isolated episode of thrombotic thrombocytopenic purpura;
- Chronic recurrent thrombocytopenic purpura.
How it manifests itself
Thrombotic thrombocytopenic purpura occurs most commonly in acute form, rapidly evolving in some days, with prodromal symptoms very variable from case to case (arthralgias, pleural pains, Raynauld's phenomenon etc.).
When an episode of TTP occurs, the following haematological changes are typically present:
- Plateletsopenia (at the medullary level, an increase in the number of megakaryocytes is observed);
- Microangiopathic hemolytic anemia : involves the fragmentation of erythrocytes ( schistocytes or helmet cells).
- High levels of serum dehydrogenase lactic acid .
The severity of these abnormalities reflects the extent of microvascular aggregation of platelets.
Furthermore, in the presence of thrombotic thrombocytopenic purpura, the patient can manifest:
- Temperature;
- Neurological symptoms (manifestations attributed to micro-thrombotic lesions of cerebral vessels):
- Confusion;
- Headache;
- Changes in behavior;
- Focal loss of sensory and motor functions: eg paresis, aphasia, disorders of the visus, muscle weakness, altered mental status, etc .;
- Embolization cerebral infarction (in some cases).
- Mucous-cutaneous bleeding symptoms:
- Small skin bleeding (petechiae and / or ecchymoses);
- Loss of blood from the nose (epistaxis);
- Bleeding gums;
- Very abundant menstrual flows;
- Rarely, organ-related bleeding occurs;
- Skin pallor or, on the contrary, purple (reddish color);
- Renal symptoms (oliguria, anuria, etc.);
- Abdominal pain, diarrhea, vomiting and pancreatic involvement (acute pancreatitis).
In severe cases of thrombotic thrombocytopenic purpura, convulsions or coma may occur.
Kidney involvement can lead to acute renal failure, while abdominal symptoms from visceral microinfarcts can simulate an acute abdomen .
In the absence of specific treatment, the mortality resulting from TTP is about 90%.
Diagnosis
TTP: how is the diagnosis made?
The diagnosis of thrombotic thrombocytopenic purpura is based on the presence of clinical symptoms and blood tests, proceeding by exclusion with respect to other similar pathologies.
At the moment, we are trying to develop a test based on the ADAMTS 13 dosage .
Thrombotic thrombocytopenic purpura: laboratory findings
In the presence of thrombotic thrombocytopenic purpura, blood tests show the following alterations:
- Platelet count: it is marked (platelet count <50, 000 units per µl) and, at the bone marrow level, an increase in the number of megakaryocytes is observed;
- Hemolytic anemia : always present, in many cases it is severe (hematocrit <20%; hemoglobin <10 g / dl). Anemia involves the detection of schistocytes at the peripheral blood smear: these cells are formed by the turbulent flow in the partially occluded areas of the microcirculation, by platelet aggregation mainly by ischemic or necrotic tissue, rather than by cell lysis. Hemolytic anemia is also associated with the presence of reticulocytosis and nucleated erythrocytes;
- Increase of LDH and indirect bilirubinemia ;
- Negative Coombs test (both direct and indirect).
Also, may be present:
- Leukocytosis with immature forms;
- High levels of blood urea nitrogen and serum creatinine;
- Reduced or indoubtable levels of haptoglobin.
Therapy
Thrombotic thrombocytopenic purpura: what are the chances of intervention?
Currently, the treatments currently available for the management of the acute episode of thrombotic thrombocytopenic purpura are:
- Plasma exchange (PEX) : transfusion procedure which consists in replacing the patient's plasma with donor plasma, in order to obtain the removal of anti-ADAMTS antibodies 13. The plasma exchange is repeated daily until the framework is normalized. Plasma exchange therapy reduces the mortality rate of TTP to 20%.
- Direct infusion of frozen plasma, always derived from donors.
These procedures may be associated with treatments with corticosteroids or immuno-suppressing drugs .
In some cases, it is necessary to intervene with the removal of the spleen ( splenectomy ) to interfere with the production of anti-ADAMTS auto-antibodies 13.
Timely and effective treatments can significantly reduce mortality. Daily transfusion therapy and drug immunosuppression induce remission of thrombotic thrombocytopenic purpura, but the possible complications related to microthrombosis remain high.
