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35-685: The presentation of TTP is variable. The initial symptoms, which force the patient to medical care, are often the consequence of lower platelet counts like purpura (present in 90% of patients), ecchymosis and hematoma. Patients may also report signs and symptoms as a result of (microangiopathic) hemolytic anemia , such as (dark) beer-brown urine, (mild) jaundice , fatigue and pallor. Cerebral symptoms of various degree are present in many patients, including headache, paresis , speech disorder, visual problems, seizures and disturbance of consciousness up to coma. The symptoms can fluctuate so that they may only be temporarily present but may reappear again later in

70-885: A TTP episode are variable but usually take less than a week in USS. The intensive plasma-therapy is generally stopped when platelet count increases to normal levels and is stable over several days. Not all affected patients seem to need a regular preventive plasma infusion therapy, especially as some reach long-term remission without it. Regular plasma infusions are necessary in patients with frequent relapses and in general situations with increased risk to develop an acute episode ( as seen above ) such as pregnancy. Plasma infusions are given usually every 2–3 weeks to prevent acute episodes of USS, but are often individually adapted. Several therapy developments for TTP emerged during recent years. Artificially produced ADAMTS13 has been used in mice and testing in humans has been announced. Another drug in development

105-503: A consequence of mechanical artificial heart valves , hemolytic uremic syndrome , and thrombotic thrombocytopenic purpura , among other causes. Excessive schistocytes present in blood can be a sign of microangiopathic hemolytic anemia (MAHA). Schistocytes are fragmented red blood cells that can take on different shapes. They can be found as triangular, helmet shaped, or comma shaped with pointed edges. Schistocytes are most often found to be microcytic with no area of central pallor. There

140-491: A full recovery of infused plasma-ADAMTS13 activity as well as a plasma half-life of infused ADAMTS13 activity of 2–4 days. A deficiency of ADAMTS13 activity in first-degree relatives is also a very strong indicator for an Upshaw–Schulman syndrome. The therapy of an acute TTP episode has to be started as early as possible. The standard treatment is the daily replacement of the missing ADAMTS13 protease in form of plasma infusions or in more severe episodes by plasma exchange . In

175-417: A later disease-onset. It has been postulated that some SNPs interact with each other and may amplify or reduce overall ADAMTS13 activity. The ADAMTS protease family contains enzymes that process collagen , cleave inter-cellular matrix , inhibit angiogenesis and blood coagulation . ADAMTS13 belongs to the zinc metalloproteases, and is mainly expressed in liver stellate cells and endothelial cells , but

210-453: A patient whom he had followed for 11 years. In his report Upshaw noted the similarities with the reported case by Schulman and hypothesized that the two cases had similar causes – a missing plasma factor. One year later, the disease was named Upshaw-Schulman syndrome. In 1996, the vWF-cleaving protease was discovered and in the following year found to be the major issue in TTP's pathogenesis. In 2001,

245-471: A schistocyte count between 3–10% is common, but >1% is suggestive of the disease. Hemolytic-uremic syndrome or HUS is hemolytic anaemia , acute kidney failure (uremia), and thrombocytopenia. HUS is caused by E. coli bloody diarrhea and specific strains of shiga toxin . The bacteria in HUS cause damage to the endothelium which results in platelet activation and formation of microthrombi. Red cells get trapped in

280-456: Is a fragmented part of a red blood cell . Schistocytes are typically irregularly shaped, jagged, and have two pointed ends. Several microangiopathic diseases , including disseminated intravascular coagulation and thrombotic microangiopathies , generate fibrin strands that sever red blood cells as they try to move past a thrombus , creating schistocytes. Schistocytes are often seen in patients with hemolytic anemia . They are frequently

315-502: Is also characteristic of a rickettsial infection. The word purpura ( / ˈ p ɜːr p ɜːr ə / ) comes from Latin purpura , " purple ", which came from ancient Greek πορφύρα. Purpura is a mass noun naming the condition or state, not the name of an individual spot (thus there is no * purpurum , * purpura or * purpura , * purpurae count declension). Schistocyte A schistocyte or schizocyte (from Greek schistos for "divided" and kytos for "hollow" or "cell")

350-449: Is based on the clinical symptoms with the concomitant presence of thrombocytopenia (platelet count below 100×10/L) and microangiopathic hemolytic anemia with schistocytes on the blood smear, a negative direct antiglobulin test ( Coombs test ), elevated levels of hemolysis markers (such as total bilirubin , LDH , free hemoglobin , and an unmeasurable haptoglobin ), after exclusion of any other apparent cause. USS can present similar to

385-453: Is caused by primary platelet activation. Thrombotic thrombocytopenic purpura leads to increased amounts of large von Willebrand factor which then attach to activated platelets and mediate further platelet aggregation. Platelets end up being removed and the resulting fibrin strand formation remains. These fibrin strands along with the stress from the blood flow cause fragmentation of the red blood cells, leading to schistocyte formation. In TTP,

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420-449: Is common with typhus and can be present with meningitis caused by meningococci or septicaemia . In particular, meningococcus ( Neisseria meningitidis ), a Gram-negative diplococcus organism, releases endotoxin when it lyses . Endotoxin activates the Hageman factor (clotting factor XII), which causes disseminated intravascular coagulation (DIC). The DIC is what appears as a rash on

455-414: Is most often found in thrombotic thrombocytopenic purpura , although they are more often seen within the range of 3–10% for this condition. A schistocyte count of <1% but greater than the normal value is suggestive of disseminated intravascular coagulation , but is not an absolute diagnosis. The standard for a schistocyte count is a microscopic examination of a peripheral blood smear . Schistocytes on

490-420: Is present an ADAMTS13 inhibitor assay is needed to distinguish between the acquired, autoantibody-mediated and the congenital form of TTP (USS). The presence of antibodies can be tested by ELISA or functional inhibitor assays. The level of ADAMTS13 inhibitor may be fluctuating over the course of disease and depends on free circulatory antibodies, therefore a onetime negative test result does not always exclude

525-463: Is targeting vWF and its binding sites, thereby reducing vWF-platelet interaction, especially on ULVWF during a TTP episode. Among several (multi-)national data bases a worldwide project has been launched to diagnose USS patients and collect information about them to gain new insights into this rare disease with the goal to optimize patient care. The incidence of acute TTP in adults is around 1.7–4.5 per million and year. These cases are nearly all due to

560-434: Is that pregnancy associated affections like pre-eclampsia, eclampsia , and HELLP syndrome can overlap in their presentation as pregnancy can trigger TTP episodes. Patients with fulminant infections, disseminated intravascular coagulation , HELLP syndrome, pancreatitis , liver disease, and other active inflammatory conditions may have reduced ADAMTS13 activity, but almost never a relevant severe ADAMTS13 deficiency <10% of

595-399: Is usually no change in deformability, but their lifespan is lower than that of a normal red blood cell (120 days). This is due to their abnormal shape which can cause them to undergo hemolysis or be removed by macrophages in the spleen. Schistocyte formation occurs as a result of mechanical destruction (fragmentation hemolysis) of a normal red blood cell. This occurs when there is damage to

630-489: The autoimmune form of TTP, where autoantibodies inhibit ADAMTS13 activity. The prevalence of USS has not yet been determined, but is assumed to constitute less than 5% of all acute TTP cases. The syndrome's inheritance is autosomal recessive , and is more often caused by compound heterozygous than homozygous mutations. The age of onset is variable and can be from neonatal age up to the 5th–6th decade. The risk of relapses differs between affected individuals. Minimization of

665-935: The TTP episode. Other unspecific symptoms are general malaise , abdominal, joint and muscle pain. Severe manifestations of heart or lung involvements are rare, although affections are not seldom measurable (such as ECG changes ). The ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13) gene is located on chromosome 9q34 and encoding 29 exons. The ADAMTS13 protease consists of 1427 amino acids and has several protein domains : Disease causing mutations in ADAMTS13 , which can be found in all ADAMTS13 protease domains. result predominantly in impaired ADAMTS13 secretion with or without decreased ADAMTS13 protease activity. More than 120 disease causing mutations and numerous single-nucleotide polymorphisms (SNP) are known today. Residual ADAMTS13 activity has been observed with certain mutations and seems to be associated with

700-541: The affected individual. Purpura are a common and nonspecific medical sign; however, the underlying mechanism commonly involves one of: Cases of psychogenic purpura are also described in the medical literature, some claimed to be due to "autoerythrocyte sensitization". Other studies suggest the local (cutaneous) activity of tissue plasminogen activator can be increased in psychogenic purpura, leading to substantial amounts of localized plasmin activity, rapid degradation of fibrin clots, and resultant bleeding. Petechial rash

735-472: The blood vessel and a clot begins to form. The formation of the fibrin strands in the vessels occurs as part of the clot formation process. The red blood cells get trapped in the fibrin strands and the shear force of the blood flow causes the red blood cell to break. The resulting fragmented cell is called the schistocyte. A normal schistocyte count for a healthy individual is <0.5% although usual values are found to be <0.2%. A schistocyte count of >1%

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770-405: The burden of disease can be reached by early diagnosis and initiation of prophylaxis if required. TTP was first recognized as a disease in 1947 and the name was given according to symptoms and underlying pathophysiology which differed from the already known immune thrombocytopenia. Irving Schulman reported a case of TTP in 1960, and Jefferson Upshaw published a paper in 1978 about relapsing TTP in

805-418: The cascade leads to thrombi formation which causes an accumulation of excess fibrin formation in the intravascular circulation. The excess fibrin strands cause mechanical damage to the red blood cells resulting in schistocyte formation and also thrombocytopenia and consumption of clotting factors. Schistocyte values between .5% and 1% are usually suggestive of DIC. Thrombotic thrombocytopenic purpura or TTP

840-535: The circulation are leading to a higher demand of ADAMTS13, which is lacking in USS, and can bring forward a TTP episode. After secretion, ADAMTS13 is either bound to the endothelial surface or free in the blood stream. The heightened shear stress in small- and microvessels alters the 3D-structure of vWF from the contracted globular form to its linear form. The linear vWF has now its active binding sites exposed, that are important to start blood coagulation . These sites bind platelets and blood vessel lesions by interlinking

875-434: The fibrin strands of the microthrombi and become sheared by the force of blood flow leading to schistocyte formation. Leaky prosthetic heart valves and other cardiac assisted devices can lead to microangiopathic hemolytic anemia (with schistocyte formation) and thrombocytopenia. The force from the blood flow over the high pressure gradient from the prosthesis leads to fragmentation of red cells, and schistocyte formation. This

910-527: The following diseases, which have to be excluded: fulminant infections , disseminated intravascular coagulation , autoimmune hemolytic anemia , Evans syndrome , the typical and atypical form of hemolytic uremic syndrome , HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, pre-eclampsia , heparin-induced thrombocytopenia , cancer that is often accompanied with metastasis , kidney injury, antiphospholipid antibody syndrome , and side effects from hematopoietic stem cell transplantation. Of note

945-443: The force of blood flow in the vessels. Disseminated intravascular coagulation or DIC is caused by a systemic response to a specific condition including sepsis and severe infection, malignancy , obstetric complications, massive tissue injury, or systemic diseases. Disseminated intravascular coagulation is an activation of the coagulation cascade which is usually a result of an increased exposure to tissue factor. The activation of

980-455: The latter the patients plasma is replaced by donated plasma. The most common sources of ADAMTS13 is platelet-poor fresh frozen plasma (FFP) or solvent-detergent plasma. The benefit of plasma exchange compared to plasma infusions alone may result from the additional removal of ULvWF. In general both plasma therapies are well tolerated, several mostly minor complications may be observed. The number of infusion/exchange sessions needed to overcome

1015-407: The normal. A severe ADAMTS13 deficiency below 5% or <10% of the normal (depending on the definitions) is highly specific for the diagnosis of TTP. ADAMTS13 activity assays are based on the direct or indirect measurement of vWF-cleavage products. Its activity should be measured in blood samples taken before therapy has started, to prevent false high ADAMTS13 activity. If a severe ADAMTS13 deficiency

1050-428: The peripheral blood smear is a characteristic feature of microangiopathic hemolytic anemia (MAHA). The causes of MAHA can be disseminated intravascular coagulation , thrombotic thrombocytopenic purpura , hemolytic-uremic syndrome , HELLP syndrome , malfunctioning cardiac valves etc. In most of the conditions, schistocytes are formed by fibrin formation and entrapment of red blood cells leading to fragmentation due to

1085-432: The presence of ADAMTS13 inhibitors and thereby an autoimmune origin of TTP. A severe ADAMTS13 deficiency in the absence of an inhibitor, confirmed on a second time point in a healthy episode of a possible USS patient, usually sets the trigger to perform a molecular analysis of the ADAMTS13 gene to confirm a mutation. In unclear cases a plasma infusion trial can be done, showing a USS in the absence of anti-ADAMTS13-antibodies

Upshaw–Schulman syndrome - Misplaced Pages Continue

1120-517: The stretched vWF with one another – a blood clot is formed. In its uncut form, (ultra large) vWF's heightened stickiness and interlinking causes spontaneous platelet binding and blood clotting. The linear vWF exposes the A2 domain, so that in the presence of enough ADAMTS13 activity it gets cut to its normal size. vWF in the normal length loses its heightened stickiness and spontaneous crosslinking activity to only form blood clots when needed. A diagnosis of TTP

1155-484: The underlying mutations. In USS severe ADAMTS13 deficiency is often not enough to induce a (first) acute TTP episode. It primarily occurs when an additional (environmental) trigger is present. Recognized triggers are infections (including mild flu-like upper airway infections), pregnancy, heavy alcohol intake or certain drugs. In these situations, vWF is released from its storage organelles , such as Weibel–Palade bodies and granules of platelets . Increased vWF levels in

1190-596: The vWF-cleaving protease was identified as ADAMTS13, the gene was mapped to chromosome 9q34, and the first USS-causing mutations were identified. Purpura Purpura ( / ˈ p ɜːr p jʊər ə / ) is a condition of red or purple discolored spots on the skin that do not blanch on applying pressure. The spots are caused by bleeding underneath the skin secondary to platelet disorders, vascular disorders, coagulation disorders, or other causes. They measure 3–10 mm, whereas petechiae measure less than 3 mm, and ecchymoses greater than 1 cm. Purpura

1225-531: Was also found in other cell types, such as platelets, podocytes in the kidney and several brain cells. The only known role of the ADAMTS13 protease is to cleave vWF multimers. The plasma half-life of administered ADAMTS13 in USS patients is around 2–4 days, whereas the protective effects seems to last longer. Usually USS patients have a severely deficient ADAMTS13 activity of <10% of the normal. In this low range there may be residual ADAMTS13 activity, depending on

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