Practical approach to thrombocytopenia in patients with sepsis: a narrative review

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Summary of Practical approach to thrombocytopenia in patients with sepsis: a narrative review

Abstract: Thrombocytopenia is common in sepsis, with disseminated intravascular coagulation (DIC) being a frequent cause, though thrombotic microangiopathy (TMA)—including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)—is increasingly recognized. Differentiating DIC from TMA is challenging due to overlapping clinical and laboratory findings. This review presents the pathophysiology, diagnosis, and treatment strategies for both conditions, introduces a new diagnostic algorithm that assesses DIC and TMA concurrently, and emphasizes early TMA identification for improved outcomes in septic patients.

Key Points

  1. Thrombocytopenia in Sepsis: Thrombocytopenia affects up to 55% of ICU patients and may stem from DIC, TMA, or other systemic illnesses, necessitating prompt differential diagnosis due to varying treatment approaches and prognostic implications.

  2. DIC Pathophysiology: DIC results from systemic coagulation activation and impaired anticoagulant responses, producing widespread fibrin clots, organ ischemia, and bleeding; NETs and histones from activated neutrophils amplify these effects through immunothrombosis.

  3. DIC Diagnosis and Treatment: Diagnosed using scoring systems like JAAM or ISTH, DIC is treated with supportive care and anticoagulants such as antithrombin or recombinant thrombomodulin in selected cases, though survival benefits in general sepsis populations are limited.

  4. TMA Classification: TMA encompasses TTP, STEC-HUS, CM-HUS, and secondary TMA, all marked by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and organ damage, with varying underlying mechanisms requiring disease-specific interventions.

  5. TTP and ADAMTS13: TTP stems from ADAMTS13 deficiency, diagnosed via enzyme activity testing or PLASMIC score, and treated with plasma exchange, corticosteroids, rituximab, caplacizumab, or recombinant ADAMTS13 depending on the etiology.

  6. HUS Subtypes and Therapy: STEC-HUS, triggered by Shiga toxin, is managed with supportive care while CM-HUS, linked to complement dysregulation, is treated with anti-C5 agents like eculizumab or ravulizumab; early intervention improves renal outcomes.

  7. Secondary TMA and Mimics: Secondary TMAs arise from drugs, cancer, pregnancy, and other systemic insults, demanding careful review of clinical context, and are managed by removing triggers and supportive measures.

  8. Other Thrombocytopenic Conditions: HLH, HIT, liver failure, and COVID-19-associated coagulopathy can mimic DIC or TMA; accurate diagnosis hinges on specific markers (e.g., hyperferritinemia, anti-PF4 antibodies, or complement levels).

  9. DIC-TMA Overlap and Crosstalk: DIC and TMA can coexist in septic patients; overlapping features complicate diagnosis, and studies show significant rates of concurrent DIC in patients with CM-HUS or secondary TMA, suggesting shared pathophysiology involving ADAMTS13 and complement systems.

  10. Proposed Diagnostic Flow: A novel diagnostic algorithm recommends simultaneous screening for DIC and MAHA to identify TMA, promoting early initiation of plasma exchange or anti-complement therapy even before definitive diagnostics are complete.

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A novel diagnosis and treatment flow for patients with thrombocytopenia associated with sepsis. Patients with sepsis-associated thrombocytopenia were checked for MAHA in the presence of TMA, in parallel with DIC diagnosis using the DIC scoring system. If TMA is suspected, a definitive diagnosis of HUS and TTP is made by confirmation of the Shiga toxin-producing ability of E. coli isolated from the patient’s stool and ADAMTS13 activity of < 10%, respectively, and PEX should be initiated. When TMA is suspected, secondary TMA may be diagnosed on the basis of the patient’s background. If neither HUS nor TTP is diagnosed, the possibility of CM-HUS should be considered. It is important to decide whether to administer an anti-C5 monoclonal antibody based on the patient’s medical condition before the results of genetic testing are known. If there are no signs of MAHA and TMA appears negative, differentiation of HIT, ITP, etc., should be performed with careful examination of the MAHA appearance. ADAMTS13, a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13; CAC, COVID-19-associated coagulopathy; CM-HUS, complement-mediated hemolytic uremic syndrome; DIC, disseminated intravascular coagulation; hapt, haptoglobin; HIT, heparin-induced thrombocytopenia; HLH, hemophagocytic lymphohistiocytosis; ITP, Immune thrombocytopenia; MAMA, microangiopathic hemolytic anemia; PCR, polymerase chain reaction; PEX, plasma exchange; rhTM, recombinant human thrombomodulin; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura; US, ultrasound

Conclusion

To avoid missing TMA in patients with sepsis-associated thrombocytopenia, clinicians must adopt a parallel diagnostic approach, identifying both DIC and MAHA early. The proposed diagnostic algorithm addresses treatment delays and real-world timeframes, offering a comprehensive strategy that may enhance diagnostic accuracy, therapeutic timeliness, and patient outcomes.

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Practical approach to thrombocytopenia in patients with sepsis: a narrative review

Watch the following video on “APPROACH TO THROMBOCYTOPENIA” by Hematology PGH

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