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Plasma Therapy. Plasma is the liquid part of your blood. It carries blood cells, hormones, enzymes, and nutrients to your body. TTP is treated with plasma therapy. This includes: Fresh frozen plasma for people who have inherited TTP. Plasma exchange for people who have acquired TTP.
How is TTP treated with plasma?
Thrombotic thrombocytopenic purpura (TTP), characterized by thrombocytopenia and microangiopathic haemolytic anaemia, was almost universally fatal until the introduction of plasma exchange (PE) therapy in the 1970s. Based on clinical studies, daily PE has become the first-choice therapy since 1991.
Is daily plasma exchange the best treatment for thrombotic thrombocytopenic purpura?
The standard treatment of acquired TTP consists mainly of daily therapeutic plasma exchange (TPE) that allows ADAMTS13 repletion and, to a lesser extent, removal of anti-ADAMTS13 antibodies and possibly pro-aggregatory substances.
What is the standard treatment for therapeutic plasma exchange (TPE)?
There is a rational basis for the use of steroids in the treatment of acquired TTP given the autoimmune origin of the disease. However, the level of proof concerning steroid efficacy in the treatment of TTP remains quite low.
Are steroids effective in the treatment of transient thrombocytopenic purpura (TTP)?
How does FFP help TTP?
Plasma exchange with fresh frozen plasma is the therapy of choice for TTP. Octaplas is a pooled plasma (human) that has been treated with a solvent detergent process. This blood product provides a viable alternative to single-donor fresh-frozen plasma, with a reduced risk of certain viral transmissions.
Why is fresh frozen plasma given in TTP?
Fresh frozen plasma is used for management and prevention of bleeding, as a coagulation factors replacement, and to treat thrombotic thrombocytopenic purpura (TTP).
What are treatment options for TTP?
Treatment options for TTP refractory to PEXCorticosteroids. Corticosteroids are used in the acute management of acquired TTP, and should be started upfront together with PEX. ... Twice-daily PEX. ... Rituximab. ... Splenectomy. ... Cyclosporine. ... Cyclophosphamide and vincristine. ... Bortezomib. ... N-acetylcysteine.More items...
What is the mechanism of TTP?
The pathophysiology of TTP involves an acute deficiency of von Willebrand factor (VWF)-cleaving metalloprotease (ADAMTS13). In idiopathic TTP, autoantibodies directed against ADAMTS13 cause enzyme dysfunction by increased clearance or impaired enzyme attachment.
How does fresh frozen plasma work?
Plasma is the liquid part of blood. It contains water, minerals, and other substances. Fresh frozen plasma (FFP) is plasma that has been frozen so it can be stored and used later. The plasma you get is thawed out and warmed before it is used.
How does fresh frozen plasma help angioedema?
Angioedema swelling occurs when bradykinin is activated in the deep layers of the skin and allows fluid to flow into the tissues of the skin from the bloodstream. So, by quickly replacing C1-INH using FFP, bradykinin production can be reduced greatly.
What is plasma dialysis?
Plasma exchange, also known as plasmapheresis, is a way to "clean" your blood. It works sort of like kidney dialysis. During the treatment, plasma -- the liquid part of your blood -- gets replaced with plasma from a donor or with a plasma substitute.
Is plasmapheresis the same as plasma exchange?
Plasmapheresis refers to a procedure in which the plasma is separated from the blood either by centrifugation or membrane filtration. Once separated the plasma can be manipulated in a variety of ways. Plasma exchange refers to discarding the plasma totally and substituting a replacement fluid.
How does rituximab work for TTP?
PEX is essential in TTP treatment as plasma contains the missing enzyme ADAMTS 13. Rituximab (licensed and internationally used monoclonal antibody) selectively acts on white blood cells known as B-lymphocytes or B cells that produce the antibody to ADAMTS 13.
What is the function of ADAMTS13 enzyme?
The ADAMTS13 enzyme cuts von Willebrand factor into smaller pieces to regulate its interaction with platelets. By processing von Willebrand factor in this way, the enzyme prevents it from triggering the formation of blood clots in normal circulation.
Which syndrome is caused by the deficiency of plasma enzyme ADAMTS13?
Congenital or acquired deficiency of ADAMTS13 can result in thrombotic thrombocytopenic purpura (see Chapter 134).
How does TTP cause microangiopathic hemolytic anemia?
TTP is caused by a deficiency in plasma ADAMTS13, which leads to the accumulation of ULVWF multimers in the microcirculation, with subsequent spontaneous platelet adhesion and aggregation and occlusive microvascular thrombosis [64]. Congenital and acquired TTP are the two clinically recognized forms of TTP.
What is thrombocytopenic purpura?
Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic end organ injury due to microvascular platelet-rich thrombi. TTP results from a severe deficiency of the specific von Willebrand factor (VWF)-cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene. In adults, the condition is most often immune-mediated (iTTP) whereas congenital TTP (cTTP) is often detected in childhood or during pregnancy. iTTP occurs more often in women and is potentially lethal without prompt recognition and treatment. Front-line therapy includes daily plasma exchange with fresh frozen plasma replacement and immunosuppression with corticosteroids. Immunosuppression targeting ADAMTS13 autoantibodies with the humanized anti-CD20 monoclonal antibody rituximab is frequently added to the initial therapy. If available, anti-VWF therapy with caplacizumab is also added to the front-line setting. While it is hypothesized that refractory TTP will be less common in the era of caplacizumab, in relapsed or refractory cases cyclosporine A, N -acetylcysteine, bortezomib, cyclophosphamide, vincristine, or splenectomy can be considered. Novel agents, such as recombinant ADAMTS13, are also currently under investigation and show promise for the treatment of TTP. Long-term follow-up after the acute episode is critical to monitor for relapse and to diagnose and manage chronic sequelae of this disease.
What is a TTP pentad?
Previously, TTP was defined by a clinical “pentad” consisting of fever, microangiopathic hemolytic anemia, thrombocytopenia, neurological deficits, and renal insufficiency [ 4 ]. However, the pentad was reported at a time before the effectiveness of plasma-based therapy in treating TTP was firmly established. Today, the presence of thrombocytopenia and MAHA alone, without an alternative explanation, should prompt serious consideration of the diagnosis of TTP or another TMA. Large cohort studies from various registries worldwide indicate that less than 10% of patients with acute TTP present with all five symptoms [ 29, 30, 31, 35, 36, 37 ]. In fact, the clinical features of acute TTP can be extraordinarily diverse and a high degree of suspicion is required to diagnose TTP and promptly initiate appropriate management [ 118 ]. The differential diagnosis for patients with possible TTP is broad and described in Table 1. In obstetric patients with TMA, hemolysis, elevated liver enzyme, and low platelet (HELLP) syndrome and preeclampsia should be ruled out prior to evaluating for other conditions such as iTTP, cTTP, or complement-mediated hemolytic-uremic syndrome (CM-HUS) [ 27, 112, 119 ].
What is cttp in chromosome 9q34?
cTTP (also known as Upshaw–Schulman syndrome OMIM 274150) is an autosomal recessive condition caused by biallelic mutations in the ADAMTS13 gene located on chromosome 9q34 [ 14 ]. Approximately 200 causative mutations have been identified in more than 150 patients, which span the entire ADAMTS13 gene [ 14, 39, 40, 41, 42, 67, 68 ]. The majority of ADAMTS13 mutations are confined to single families [ 40, 42 ]. Missense mutations are most common (59%), followed by nonsense mutations (13%), deletions (13%), splice site mutations (9%), and insertions (6%) [ 67 ]. There is some geographic variability and certain mutations have increased frequency in different regions. Two mutations in particular, p.R1060W [ 39, 41, 42, 68, 69, 70, 71, 72] and insertion c.4143_4144dupA [ 42, 68, 69, 73] are more prominent in cTTP patients with European ancestry. The p.R1060W mutation, a single nucleotide variant located on exon 24, also occurred in a high proportion (75–80%) of cTTP patients that presented during pregnancy in the French and UK cohorts [ 70, 71 ]. Though no definite genotype–phenotype relationships have been established [ 41, 67 ], earlier onset of disease appears to be related to earlier sequence mutations in the prespacer region of ADAMTS13 [ 41, 72, 74 ]. Often, mutations in ADAMTS13 result in secretion deficiencies but they can also affect ADAMTS13 activity [ 67, 74, 75, 76 ]. Indeed, in an effort to explain the variance of clinical phenotype, residual ADAMTS13 activity of different genotypes was measured and the results showed that residual ADAMTS13 activity <3% was correlated with earlier age of disease onset, need for prophylactic plasma infusions, and an annual event rate >1 [ 42, 74 ]. However, this does not fully explain the phenotypic differences in cTTP as studies have demonstrated that many patients homozygous for the c.4143_4144dupA mutation had ADAMTS13 activity <1% but widely varying clinical courses [ 42, 69, 73 ].
How long did Purpura die?
Eli Moschcowitz described a previously healthy 16-year-old girl who became acutely ill with fever, weakness, focal neurological symptoms, and severe thrombocytopenia. Ultimately, she became comatose and died after one week.
What is a TMA?
Thrombotic microangiopathy (TMA) is a broad term which has both pathologic (occlusive microvascular or macrovascular disease commonly with intraluminal thrombus formation) and clinical (microangiopathic hemolytic anemia (MAHA) with thrombocytopenia) definitions [ 26, 27 ]. The different entities presenting with TMA findings have historically been difficult to distinguish from one another, but elucidating the pathophysiology of TTP has allowed for more accurate differentiation. As a result, standard definitions and terminology have been adopted [ 27, 28 ].
What are the two categories of anti-ADAMTS13?
Anti-ADAMTS13 autoantibodies are largely divided into two categories: inhibitory and non-inhibitory. Inhibitory antibodies neutralize the proteolytic activity of ADAMTS13 and non-inhibitory antibodies bind to the protease, accelerating its clearance from plasma [ 11, 12, 82, 83, 84 ]. It was previously widely held that inhibitory antibodies were the main cause of ADAMTS13 deficiency, but recent studies have demonstrated that antigen depletion also significantly contributes to deficiency [ 85 ]. Even a small amount of anti-ADAMTS13 autoantibodies can induce ADAMTS13 deficiency [ 86 ]. Anti-ADAMTS13 autoantibodies have been found against all domains of ADAMTS13, indicating a polyclonal immune response. However, the spacer domain of ADAMTS13 has been identified as an immunogenic region, as anti-spacer antibodies are present in most iTTP patients [ 85, 86, 87, 88, 89, 90, 91, 92 ]. Recently, anti-ADAMTS13 autoantibodies that induce the open conformation of ADAMTS13 have been identified [ 18, 93 ]. The role these conformation-changing antibodies play in the pathophysiology of TTP and their clinical significance is still being explored.
What is the function of ADAMTS13?
ADAMTS13 is a critically important enzyme, synthesized in hepatic stellate cells [ 43, 44 ], whose only known function is to regulate VWF multimers [ 9, 10 ]. In physiologic conditions, ADAMTS13 is in a latent, closed conformation and VWF, secreted by platelets and endothelial cells, is in a globular state ( Figure 1 a) [ 45, 46 ]. Proteolytic activity of ADAMTS13 on VWF is dependent on the conformational change of both proteins [ 45, 46, 47, 48, 49, 50 ]. Under shear forces VWF unravels and exposes its A1 domain allowing for interaction with platelets through the GpIb/IX/V complex ( Figure 1 b) [ 51, 52, 53 ]. In this unraveled state, the A2 domain of VWF is elongated and exposes the ADAMTS13 binding sites [ 48, 50] and the cleavage site Tyr1605-Met1606 [ 9, 10 ]. Initial interaction of CUB1-2 domains with VWF D4-CK domains allosterically activates ADAMTS13, inducing an open conformation ( Figure 1 c) [ 47, 49 ]. Sequential exosite interactions and binding of the disintegrin-like domain of ADAMTS13 to VWF induces further allosteric activation of the metalloprotease domain which results in proteolysis ( Figure 1 d) [ 54 ]. When severe ADAMTS13 deficiency (<10%) is present, ULVWF multimers can accumulate leading to unregulated platelet adhesion and aggregation, resulting in TTP with disseminated microthrombi and organ ischemia [ 4, 7, 26 ].
What is therapeutic plasma exchange?
Therapeutic plasma exchange has been established as proven first-line therapy for TTP, with an ASFA category I indication as previously mentioned. It has been shown to significantly reduce overall mortality from >90% when untreated to <10% with proper management. Once a clinical diagnosis has been made, plasma exchange should be initiated as soon as possible, as patients with TTP can deteriorate rapidly and abruptly. Exchanges are typically performed using multiple donor plasma units such as FFP or FP24. It should be noted here that ADAMTS13- related testing is complex and is usually performed by larger reference laboratories. Turnaround times on such results may be on the order of days, and therefore treatment for TTP should not be delayed while awaiting these results. It is advisable, however, to secure a blood sample for ADAMTS13 testing prior to infusion of donor plasma.
What is the pathophysiology of TTP?
The pathophysiology of TTP stems from a deficiency of the ADAMTS13 metalloprotease enzyme, which has the normal in-vivo function of cleaving unusually-large von-Willebrand factor multimers into smaller circulating forms . In TTP, autoantibodies with specificity for ADAMTS13 can be formed, which inhibit its enzymatic activity and lead to a functional deficiency. Severe ADAMTS13 deficiency with less than 10% activity and the presence of inhibiting antibodies can be demonstrated by laboratory assays in the majority of TTP cases.
How much plasma is needed for apheresis?
The typical apheresis treatment regimen for TTP consists of repeated, daily plasma exchanges. These usually process between 1 to 1.5 plasma volumes per procedure. An example calculation of a single plasma volume is shown here for a 70kg male with a hematocrit of 45%, which amounts to approximately 2.7 liters of plasma. This translates to replacement with approximately 8 units of donor plasma, assuming a volume of 350mL per unit. If circumstances preclude timely initiation of plasma exchanges, donor plasma infusions should be started at a dose around 30 mL/kg with the minimum goal of functional ADAMTS13 repletion. Plasma exchange is ultimately still the definitive therapy, and therefore plasma infusions should only be a temporizing measure.
How is apheresis done?
A patient’s efferent and afferent vascular access is obtained either through venous central access catheters or through venous peripheral access with large-bore needles able to withstand relatively high pressures and flow-rates. The whole blood that is initially removed from the patient is separated in the apheresis machine, commonly through continuous centrifugation, which separates out blood components such as red blood cells, buffy coat layer, and plasma based on relative density. The machine can be programmed to remove a specific component, such as the plasma layer . When the remaining components are returned to the patient, replacement fluids are added to the return line, depending on the specific indication. Calcium can also be added to the return line to offset the effects of the citrate anticoagulant used throughout the process.
What is the difference between TTP and ADAMTS13?
Under normal circumstances ADAMTS13 cleaves von-Willebrand factor into smaller functional fragments . Platelets are able to pass through the microvasculature without abnormal activation. In TTP, however, autoantibodies interfere with the normal action of ADAMTS13 and lead to a functional deficiency. The unusually-large von-Willebrand factor multimers remain non-cleaved, which interact with the local endothelium and passing platelets. These interactions in the high-shear flow microvascular environment activate a pro-thrombotic state, leading to occlusive thrombus formation rich in both platelets and von-Willebrand factor.
What are the features of TTP?
The classic teaching is that patients with TTP present with a pentad of features stemming from the thrombotic microangiopathy, including: thrombocytopenia, microangiopathic hemolytic anemia, neurologic changes, renal dysfunction, and fever. In reality, this entire pentad is rarely encountered, and other signs or symptoms such as abdominal pain may be prominent.#N#Therefore TTP remains largely a clinical diagnosis based on the available information and a clinician’s index of suspicion. In the absence of other plausible causes, thrombocytopenia and microangiopathic hemolytic anemia may be enough to render the provisional diagnosis of TTP until proven otherwise.
What is the consequence of ADAMTS13 deficiency?
The ultimate consequence of ADAMTS13 deficiency is the widespread formation of microvascular thrombi. This deficiency leads to an increased amount of circulating unusually- large von-Willebrand multimers, which physically interact with platelets and endothelial cells in high-shear flow environments such as the arterial microvasculature. This interaction leads to local activation of pro-thrombotic physiology and the formation of platelet and von-Willebrand factor-rich thrombi. Ischemic end-organ damage then ensues, manifesting in widespread locations such as the cerebral and renal microvasculature.
What is the treatment for TTP?
WHATIS THE TREATMENT FOR TTP? For patients with inherited TTP(inherited ADAMTS13 deficiency), simple infusion of plasma in sufficient. Most children and adults only need plasma infusion when they have some illness which may trigger an episode of TTP.
When was plasma exchange first used?
In the era before plasma exchange was first used in the 1970s, only 10% of patients survived. With the initial use of PEX, survival increased from 10% to 80%. PEX is done with a machine that removes patient plasma and replaces it with fresh plasma, similar to the machines used for routine blood donations.
How long after delivery can you continue plasma exchange?
We then continue the plasma infusion for 6 weeks after delivery, because the postpartum period is also a risk. For patients with acquired TTP, plasma exchange (abbreviated as PEX) is the most important treatment. In the era before plasma exchange was first used in the 1970s, only 10% of patients survived.
Can infused plasma cause hives?
Allergic reactions to the infused plasma are common; most reactions cause only hives, but some can also cause breathing problems. We continue plasma exchange daily until the platelet count is normal. Then we stop. If the TTP is still active, the platelet count will fall again and daily treatments must be resumed.
What is the treatment for acquired TTP?
The standard treatment of acquired TTP consists mainly of daily therapeutic plasma exchange (TPE) that allows ADAMTS13 repletion and, to a lesser extent, removal of anti-ADAMTS13 antibodies and possibly pro-aggregatory substances. TPE transformed the historically fatal prognosis of TTP, leading to the current overall survival rates of 80%-85%. 2 In the last several years, further significant changes have been introduced in the management of acquired TTP. The identification of the central role of anti-ADAMTS13 antibodies in the pathophysiology of TTP, 3 which is now considered an autoimmune disease, has led to wider use of immunosuppressive treatments. In this context, the introduction of rituximab has probably been the second major breakthrough in TTP management. However, the current knowledge about the use of rituximab in TTP is based on few studies with a limited number of patients and moderate levels of evidence. Moreover, these studies raised many questions that remain unsolved. Should rituximab be used as frontline therapy, or only in patients with a suboptimal response to TPE? Which is the optimal schedule of rituximab administration? Should rituximab be systematically used as preemptive therapy? Which strategy should be used when rituximab fails to improve ADAMTS13 activity? Lastly, there is no consensus concerning the management of patients with refractory disease and emerging therapies might bring new weapons to our therapeutic arsenal in the future years. These topics are addressed in this review.
What antiplatelet agents are used in TTP?
The use of antiplatelet agents in TTP is based on the rationale that the main pathological feature of the disease is the presence of platelet thrombi in the microcirculation. Aspirin and dipyridamole are the 2 main compounds considered to be potentially effective for TTP treatment. However, in TTP, the main mechanism of platelet clumping involves the glycoprotein Ib-IX/von Willebrand factor (vWF) axis. This challenges the relevance of aspirin and dipyridamole in TTP treatment because their mechanism of action involves other pathways. This discrepancy may account for the variability in the tolerance and results reported by the clinical trials that evaluated the efficacy of these antiplatelet agents in TTP (for a review, see Coppo and Veyradier 1 ).
How often should TPE be performed?
In France, the TPE procedure usually requires 1.5× plasma volume exchange with only plasma for the first procedures, and subsequently a 1.0× plasma volume replacement combined with 0.5×x 4% albumin. TPE is performed daily until organ involvement has resolved and the platelet count has stably recovered (ie, a normal platelet count for at least 2 consecutive days). Whether TPE sessions after remission is achieved should be stopped rapidly or tapered to prevent sudden exacerbations remains a matter of debate.
What is thrombocytopenic purpura?
Thrombotic thrombocytopenic purpura (TTP) is a particular form of thrombotic microangiopathy (TMA), character ized typically by microangiopathic hemolytic anemia, profound peripheral thrombocytopenia and severe deficiency in the von Willebrand factor-cleaving protease ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin-1 motifs; 13 rd member of the family). ADAMTS13 deficiency is usually severe (<10%) and results from autoantibodies against ADAMTS13 (acquired TTP) or from biallelic mutations of the encoding gene. In some cases, acquired TTP occurs in association with specific conditions that have to be identified for appropriate management: HIV infection, connective tissue disease, pregnancy, cancer, or treatment with antiplatelet agents. 1
How long does it take for rituximab to work?
Importantly, rituximab might not be effective for the treatment of unresponsive TTP during the first 2 weeks, with a reported delay in the onset of its effect that may reach 27 days. 7
How long does it take for a TTP to respond to steroids?
Thirty patients (55%) responded to steroids in 48-72 hours, whereas the remaining 24 patients did not improve and required TPE. 4 This study, which was performed before the current systematic use of TPE in TTP, indicates that the administration of high-dose steroids alone has some efficacy in the treatment of TTP, at least in patients without significant organ involvement. A prospective randomized study on 60 patients compared the effectiveness of standard-dose (1 mg/kg/d) and high-dose methylprednisolone (10 mg/kg/d for 3 days and then 2.5 mg/kg/d) as an adjunctive treatment to TPE in patients with newly diagnosed TTP. After 23 days of treatment, complete remission was not achieved in 23% of patients in the high-dose methylprednisolone group and in 53% of patients of the standard-dose group. Although this study did not answer the question of whether steroids increase the likelihood of remission compared to treatment without steroids, it suggests that high-dose steroid therapy improves the management of TTP. 5 Together, these results indicate that steroids might have a place in the management of TTP in association with TPE, provided there is no obvious contra-indication. However, the modality of administration remains debatable.
Why is TTP difficult to diagnose?
The diagnosis of TTP in an emergency setting is challenging because the disease is rare, which may lead to a delay in management that can impact the prognosis. Consequently, there is a crucial need to develop educational programs for generalists, emergency department physicians and all other specialists possibly involved in the management of TTP, to improve the diagnosis and the treatment of the disease. In addition, there should also be educational programs for patients about the typical features suggestive of a relapse.
What is TPE in plasma?
With certain diseases, plasma can contain an abnormal substance that may trigger symptoms. TPE helps remove this abnormal substance and relieve symptoms. TPE can also help you better fight your disease. TPE is also known as plasmapheresis.
How does a plasma machine work?
The machine separates blood into its various parts. It then removes the plasma. The machine adds a plasma substitute to the remaining blood. This may be a replacement fluid that contains saline and albumin. Or it may be plasma from a human donor. The blood containing the new plasma returns to you through the tubing.
What is TPE in medical terms?
Therapeutic plasma exchange (TPE) is a treatment that removes plasma from your blood. The removed plasma is then replaced with a substitute. Plasma is the liquid portion of blood. It helps carry blood cells and other substances throughout your body. With certain diseases, plasma can contain an abnormal substance that may trigger symptoms.
How long does it take for a TPE to work?
You often need more than one treatment. You and your healthcare provider will discuss the schedule for your treatment in advance. Each plasma exchange takes about 2 to 4 hours.
Why is there a risk of infection when you have a non-plasma replacement fluid?
Increased risk for infection because your normal immune system proteins (antibodies) have been removed. Too little calcium in the blood (hypocalcemia) When non-plasma replacement fluid is used: too little potassium in the blood (hypokalemia) When donor plasma is used: Allergic reaction or disease transmission.
Why do we use TPE?
Why TPE is done. TPE is most often used to treat certain blood, neurologic, or autoimmune diseases. Examples are: Used alone, TPE cannot cure these diseases. But it may help slow their progress and relieve symptoms. When used with other treatments, TPE may increase your chances of fighting the disease.
Can TPE cure Goodpasture syndrome?
Myasthenia gravis. Some diseases of the kidney such as Goodpasture syndrome. Used alone, TPE cannot cure these diseases. But it may help slow their progress and relieve symptoms. When used with other treatments, TPE may increase your chances of fighting the disease.