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Haematological Disease
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Haemolysis occurs in small blood vessels due to a variety of causes. Haemolytic–uraemic syndrome (HUS): Platelet and endothelial damage is related to toxigenic Escherichia coli infection.Thrombotic thrombocytopenic purpura (TTP): Damage is related to inherited or acquired deficiency of a protease (ADAMTS13) that normally cleaves very large forms of vWF.
Immunohematology
Published in Gabriel Virella, Medical Immunology, 2019
Gabriel Virella, Armand Glassman
Thrombotic Thrombocytopenia (TTP) is a rare coagulation disease that exists in acquired (most commonly) and inherited forms. The acquired form is caused by antibodies that inhibit ADAMTS13, a metalloproteinase with thrombospodin type I motif enzyme that cleaves large multimers of von Willebrand factor (vWF). In the absence of ADAMTS13 activity, thrombosis due to the residual large multimers of vWF result in the formation of small platelet clots which adhere to endothelial surfaces blocking vessels. The circulating red blood cells passing through the clots are subjected to sheer stress Platelets are consumed in the thrombi resulting in the combination of thrombocytopenia and thrombosis and the sheer stress of the red cell results in the formation of schistocytes, anemia, and renal failure.
Haemostasis: Normal Physiology, Disorders of Haemostasis and Thrombosis
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Elizabeth Jones, Russell David Keenan
Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening condition that requires urgent treatment when recognized. It is a haematological emergency. Patients present haematologically with low platelets and anaemia (due to haemolysis) with fragments of red cells (schistocytes) seen on blood film, a microangiopathic haemolysis. Patients can have clinical symptoms of fever and neurological features (confusion, seizures) along with renal failure. In TTP the low platelets are caused by thrombosis in small blood vessels. The fibrin strands act as a ‘cheese wire’ leading to the red cell fragments. The underlying pathology is a reduction in a protein called ADAMTS13, which is normally involved in controlling vWF. With reduced ADAMTS13 vWF builds up into even bigger multimers than normal. The molecules can even get to the size of cells. Treatment is aimed at the underlying cause, reducing the abnormal vWF molecules and also replacing ADAMTS13. At the moment this is most effectively done by plasma exchange. Steroids and further immunosuppressive agents are also needed to gain control of the underlying drivers in the acquired form (there is a congenital variant of the condition with deficiency of ADAMTS13 and replacement by plasma infusion is sufficient treatment). When the platelet count rises thromboprophylaxis should be instigated as thrombosis is common in recovery.
An update on novel therapies for treating patients with arterial thrombosis
Published in Expert Review of Hematology, 2023
Udaya S Tantry, Sanchit Duhan, Eliano Navarese, Bogumil Ramotowski, Parshotam Kundan, Kevin P Bliden, Paul Gurbel
Animal experiments demonstrated that inhibition of A1 domain by humanized anti-VWF-A1 blocking nanobody named caplacizumab (ALX-0081) can inhibit platelet binding to VWF under shear and acute thrombosis without any effect on hemostasis [42]. The clinical development of caplacizumab in arterial disease patients was discontinued due to severe bleeding risk. However, caplacizumab is the first humanized, bivalent nanobody approved for treatment in patients with thrombotic thrombocytopenic purpura (TTP). Caplacizumab binds to A1 domain of VWF thereby inhibits VWF-mediated platelet adhesion and aggregation and concomitant reduction of blood clotting factor VIII. In patients with TTP, the ability of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif) to cleave ultra-large multimers of VWF is inhibited by autoantibodies (enzyme activity < 10%) leading to platelet consumption in VWF-platelet aggregates and microvascular thrombosis. In the phase III HERCULES, subcutaneous administration of caplacizumab on top of current therapy in patients with TTP demonstrated faster resolution of the disease, fewer TTP-related deaths and less recurrence of the disease [43].
An update on the pathogenesis and diagnosis of thrombotic thrombocytopenic purpura
Published in Expert Review of Hematology, 2023
Inés Gómez-Seguí, Cristina Pascual Izquierdo, María Eva Mingot Castellano, Javier de la Rubia Comos
ADAMTS13 deficiency can be hereditary (hTTP) or acquired of immune origin (immune-mediated, iTTP). The ADAMTS13 gene is located in chromosome 9 (locus 9q34) and the most common cause of hTTP are missense mutations [3], while iTTP is the consequence of the development of autoantibodies able to block ADAMTS13 activity or to accelerate its clearance [4]. The incidence and prevalence of iTTP are 1.5–6.0 cases per million inhabitants per year [5–8] and 13–19 cases per million inhabitants [5,7], respectively. The first episode usually occurs between 30 and 50 years of age in Europe and the USA and is close to 60 years of age in Japan [9,10]. Pediatric cases represent only 10% of the cases, with an annual incidence of 0.09 cases per million [7,11]. TTP affects women more often (55% to 79% of the cases) [5,9,11,12]. In adults, iTTP is close to 30 times more frequent than hTTP; however, among pediatric patients, the hereditary form is much more common [8,11,13]. Known triggers for acute TTP episodes are pregnancy, autoimmune diseases, infections, cancer, or drugs [5–9].
Predictors of relapse and preventative strategies in immune thrombotic thrombocytopenic purpura
Published in Expert Review of Hematology, 2021
Katerina Pavenski, Shih-Han Susan Huang, Christopher J. Patriquin
A summary of an iTTP episode, along with possible outcomes, is presented in (Figure 1). With or without a precipitating trigger, patients develop clinical evidence of iTTP. Following diagnosis and appropriate treatment, most patients reach clinical response, defined as normalization of platelet count and hemolytic markers and no evidence of new organ injury [13]. With current therapy, less than 3% of the patients will die [9]. After reaching a clinical response, the majority of patients (about 80%) will attain normal ADAMTS13 levels (i.e. ‘ADAMTS13 remission’) and enter remission. Approximately 20% will have persistent deficiency and remain at high risk of exacerbation [11,14,15]. These patients are usually treated with intensified immunosuppression, with most eventually achieving clinical and ADAMTS13 remission. Based on the authors’ experience, a small minority (<5%) will not improve with time and/or treatment and will have persistent ADAMTS13 deficiency; these patients are at a very high risk of relapse. Moreover, patients with persistently abnormal ADAMTS13 activity in remission are at a higher risk of developing stroke, even in the absence of clinical relapse [16]. Whether they also experience clinically silent progression (e.g. neurocognitive deficits) is unknown.