Learning Objectives

By the end of this presentation, the clinician will be able to:

1. Create an appropriate differential diagnosis of thrombotic thrombocytopenic purpura in the presence of microangiopathic hemolytic anemia and acute periph­eral thrombocytopenia.

2. Evaluate the different components of the medical history and physical examina­tion, which indicate the most appropriate order within the differential diagnosis and hence a correct course of further diagnostic procedures needed to reach a denitive diagnosis.

TTP (thrombotic thrombocytopenic purpura) is a kind of thrombotic microangi­opathy (TMA) characterized by severe cytopenia (thrombocytopenia and hemo­lytic anemia). Additionally, extensive microvascular thrombi in TTP cause multi-organ failure of varying severity with a 20% death rate [1]. A signicant deciency of the von Willebrand factor-cleaving protease ADAMTS13

(ADisintegrin And Metalloproteinase with ThromboSpondin-1 motifs, 13th mem­ber) causes the accumulation of large multimers of von Willebrand factor (ULVWF) in plasma. The presence of a signicant ADAMTS13 deciency is currently con­sidered part of a positive diagnosis [1, 2]. TTP is a deadly disease that necessitates prompt diagnosis and treatment in the event of an emergency. TTP, on the other hand, might be difcult to diagnose in an emergency environment because of its rarity (4 instances per 106 people per year) [3]. Furthermore, because TTP is char­acterized by peripheral cytopenias, it can be confused with other conditions, par­ticularly autoimmune cytopenias (AIC) , such as autoimmune thrombocytopenia associated or not with autoimmune hemolytic anemia (Evans syndrome) , which adds to the difculty of obtaining a positive diagnosis [4]. In this context, deter­mining the activity of ADAMTS13 is particularly useful in determining the diag­nosis of TTP in patients with peripheral cytopenias [5]. However, in cases of diagnosis ambiguity, a quick ADAMTS13 activity evaluation is not routinely accessible in all centers, resulting in diagnostic inconclusiveness with potentially severe repercussions on prognosis by delaying therapeutic plasma exchange (TPE). As a result, it is critical to pinpoint the factors that lead to TTP misdiagnosis using AIC, as well as the implications for prognosis. A retrospective multicenter study was conducted, allowing for the retrograde analysis of the outcomes of these mis­diagnoses and understanding the causes or missed events that led to a misdiagnosis in these cases.

Thrombotic thrombocytopenic purpura was misdiagnosed based on the following observations:

remained comparable between the two groups. Importantly, misdiagnosed patients are de facto selected patients who survived misdiagnosis’s consequences, and it can­not be ignored that some patients with an AIC misdiagnosis succumbed to the illness before TTP was diagnosed and thus were not disclosed in the registry, potentially underestimating the death rate and incidence of misdiagnosed patients. There are various factors responsible for TTP misdiagnosed with AIC.The higher frequency of AIC, which is three to eight times that of TTP [9], and the relatively recent availabil­ity of ADAMTS13 as a viable technique for distinguishing TTP from other disorders both contribute to diagnostic inaccuracies. Furthermore, identifying a microangio­pathic hemolytic anemia can prove to be complicated, especially in an emergency situation; indeed, in a large group of patients, schistocytes were found to be low or nonexistent in more than one-third of cases at rst presentation, but positive in the days following. In 10% of all patients, a positive, low titer DAT that implies the diag­nosis of autoimmune hemolytic anemia might be found, which adds to the difculty of diagnosing microangiopathic hemolytic anemia. Positive DAT was noted anecdot­ally in the correctly identied group (5% of cases), which is consistent with prior reports from other groups [6]. Almost 20% of patients in the misdiagnosed group had a positive DAT.Further research is needed to examine the characteristics of antibod­ies directed against erythrocytes in these individuals, notably their specicity via elution, in order to truly comprehend their pathogenic implications. This unantici­pated outcome might be attributed in part to improved knowledge of TTP diagnosis, enabling the detection of occurrences of TTP that were previously undetected prior to the availability of ADAMTS13. These two confounding factors thus characterize a subpopulation of patients with traditional AIC symptoms (low/absent schistocytes and a positive DAT at rst presentation; 10% of the overall TTP population) for whom TTP diagnosis is incredibly complex. Findings from this study suggest that a positive DAT should not be used to rule out TTP diagnosis. Furthermore, in patients with peripheral cytopenias, a repeated and more comprehensive search for schisto­cytes should be performed to reduce the chance of misdiagnosis, particularly in patients with organ failure, when the diagnosis of TTP should be clearly favored until ADAMTS13 activity is known. As per this statement, despite organ involvement that should have suggested TTP, a disproportionately high number of TTP patients previ­ously diagnosed with an AIC were detected. Interestingly, nearly half of misdiag­nosed patients had a cerebral involvement, while neurologic events in AIC are extremely rare (1–4% of cases) [10, 11] and are mostly precipitated by intracranial hemorrhage. The emergence of cerebral sequelae following an initial diagnosis of AIC was the primary cause for diagnosis revision, which led to the denitive diagno­sis of TTP in the current investigation. Although the number of misdiagnosed patients has declined with time, indicating that TTP has become much more well-recognized than in the past, there are still a substantial number of misdiagnoses. These ndings suggest that vigorous awareness campaigns for practitioners who may be involved in the diagnosis of TTP, such as intensivists and urgent care physicians, hematologists, internists, and nephrologists, as well as general practitioners, should be undertaken. National policies should support awareness efforts focused on enhancing TTP diag­nosis and early management in order to improve a broad understanding of these uncommon illnesses [10, 12] and provide practitioners with a resource activity [13].

AdedamolaBello

Learning Objectives

By the end of this presentation, the clinician will be able to:

4. Discuss the impact of the delayed diagnosis on prognosis, inappropriate man­agement, and quality of life for patients.

5. Discuss and enumerate the diagnostic approach to fatigue and weakness and the appropriate investigations to elucidate the etiology of the illness.

TTP (thrombotic thrombocytopenic purpura) is a rare life-threatening blood dis­order marked by several clinical signs and symptoms, including microangio­pathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal dysfunction, and neurologic abnormalities [1, 2]. The majority of the time, clinical

practitioners consider TTP when patients have thrombocytopenia, increased lac­tic dehydrogenase (LDH), and schistocytes in a peripheral blood smear test, albeit schistocytes may be nonexistent at the onset of the disease. If TTP is sus­pected, treatment should commence with exchange plasma transfusion [3], which necessitates the installation of a central venous catheter (CVC) [4]. Clinically, thrombotic microangiopathies (TMAs) are usually challenging to distinguish, and measuring ADAMTS13 (a disintegrin and metalloproteinase with a thrombo­spondin type 1 motif, member 13) is still crucial for the diagnosis of TTP. In areas of Asia and the Mediterranean region, as well as in nations where people migrate from these regions, hemoglobin H illness is common [1]. Compound heterozy­gosity for both ɑ+ -thalassemia (resulting from the deletion of one ɑ-globin gene), which is common and has carrier rates as high as 70% in some regions of the world [ 2], and ɑ0 -thalassemia (resulting from the deletion of two globin genes in cis), which was previously only seen in populations from specic regions [2] but is now being seen in other ethnic groups, is present in patients with this disease [1]. Rarely can point mutations in the gene that codes for ɑ+ -globin cause ɑ