SARS-CoV-2 Vaccination and Immune Thrombocytopenia in de novo and pre-existing ITP patients

Cases of de novo immune thrombocytopenia (ITP) - including a fatality - following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in pre-existing ITP. In this study, four data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a ten-center retrospective study of adults with pre-existing ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA, United States) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] x109/L approximately 1-week post-vaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 109 patients with pre-existing ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30x109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK ITP patients, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in pre-existing ITP or be identified de novo post-SARS-CoV2-vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those post-splenectomy and with more refractory disease, is indicated.

Oseltamivir improved thrombocytopenia during veno-arterial extracorporeal membrane oxygenation in adults with refractory cardiac failure: A single-center retrospective real-world study

Background Severe thrombocytopenia is a common complication of extracorporeal membrane oxygenation (ECMO). Oseltamivir can be used to treat infection-associated thrombocytopenia. Objective To evaluate the effect of oseltamivir on attenuating severe thrombocytopenia during ECMO. Methods This was a single-center real-world study in critically ill patients supported with venous-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients suspected or confirmed with influenza received oseltamivir according to the Chinese guidelines. Thrombocytopenia and survival were compared between the oseltamivir-treated and -untreated groups. The factors associated with survival were analyzed by multivariable Cox analysis. Results A total of 82 patients were included. All patients developed thrombocytopenia after initiating VA-ECMO. Twenty-three patients received oseltamivir (O+ group), and 59 did not (O− group). During the first 8 days of VA-ECMO initiation, the platelet counts in the O+ group were higher than in the O− group (all P < 0.05). The patients in the O+ group had higher median platelet counts at the nadir (77,000/µL, 6,000-169,000/µL), compared with the O− group (49,000/µL, 2,000-168,000/µL; P = 0.04). A platelet count nadir < 50,000/µL was seen in 26% of the patients in the O+ group, compared with 53% in the O− group (P = 0.031). No significant differences in survival to discharge were seen between the O+ and O− groups (48% vs. 56%, P = 0.508). Only the Sequential Organ Failure Assessment (SOFA) scores at the time of VA-ECMO initiation were independently associated with survival (OR = 1.12, 95% confidence interval (95% CI): 1.02–1.22, P = 0.015). Conclusions Oseltamivir could ameliorate VA-ECMO-related thrombocytopenia. These findings suggest the prophylactical potential of oseltamivir on severe thrombocytopenia associated with the initiation of VA-ECMO.

Oseltamivir improved thrombocytopenia during veno-arterial extracorporeal membrane oxygenation in adults with refractory cardiac failure: A single-center retrospective real-world study

Background Severe thrombocytopenia is a common complication of extracorporeal membrane oxygenation (ECMO). Oseltamivir can be used to treat infection-associated thrombocytopenia. Objective To evaluate the effect of oseltamivir on attenuating severe thrombocytopenia during ECMO. Methods This was a single-center real-world study in critically ill patients supported with venous-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients suspected or confirmed with influenza received oseltamivir according to the Chinese guidelines. Thrombocytopenia and survival were compared between the oseltamivir-treated and -untreated groups. The factors associated with survival were analyzed by multivariable Cox analysis. Results A total of 82 patients were included. All patients developed thrombocytopenia after initiating VA-ECMO. Twenty-three patients received oseltamivir (O+ group), and 59 did not (O− group). During the first 8 days of VA-ECMO initiation, the platelet counts in the O+ group were higher than in the O− group (all P < 0.05). The patients in the O+ group had higher median platelet counts at the nadir (77,000/µL, 6,000-169,000/µL), compared with the O− group (49,000/µL, 2,000-168,000/µL; P = 0.04). A platelet count nadir < 50,000/µL was seen in 26% of the patients in the O+ group, compared with 53% in the O− group (P = 0.031). No significant differences in survival to discharge were seen between the O+ and O− groups (48% vs. 56%, P = 0.508). Only the Sequential Organ Failure Assessment (SOFA) scores at the time of VA-ECMO initiation were independently associated with survival (OR = 1.12, 95% confidence interval (95% CI): 1.02–1.22, P = 0.015). Conclusions Oseltamivir could ameliorate VA-ECMO-related thrombocytopenia. These findings suggest the prophylactical potential of oseltamivir on severe thrombocytopenia associated with the initiation of VA-ECMO.

P0248HEPARIN-INDUCED THROMBOCYTOPENIA (HIT): A POSSIBLE CAUSE OF VENOUS THROMBOEMBOLISM IN ACTIVE SYSTEMIC VASCULITIS

Background and Aims Increased incidence of venous thromboembolism in active phase of vasculitis has been found by several authors. Examining large cohorts of patients, the underlying mechanisms still remain unclear. Patients with active vasculitis are not rarely exposed to heparin mainly because of dialysis, plasmafiltration or ECMO. In the high inflammatory context of active vasculitis, as in major surgery, heparin exposure could promote the formation of anti-PF4/heparin antibodies and induce HIT. Method Description of cases with active vasculitis and HIT observed in our cohort of ANCA-associated vasculitis patients from 1994 to 2019. Review of cases reported in the literature. Results We observed 18 patients with systemic vasculitis and HIT (10 M and 8 F, median age: 69.5 yo). Fourteen had ANCA antibodies, one patient had both ANCA and anti-GBM antibodies (double positive), two had positive anti-GBM antibodies, one had negative ANCA and anti-GBM antibodies. Among 15 patients with positive ANCAs, 13 had anti-MPO antibodies and 2 anti-PR3 antibodies (Fig. 1). All patients were exposed to heparin, 10 because of plasmafiltration and dialysis, 8 for dialysis alone. Mean platelet count nadir was 76100/mm3 (range 23000-197000/mm3). In all patients PF4–heparin antibody immunoassay was strongly positive (optical density &gt;1 in 13 patients). The most frequent manifestations were thrombocytopenia and repeated clotting of the extracorporeal circuit and dialyzer with thrombosis of the hemodialysis catheter (6/18 patients). Four patients developed deep vein thrombosis almost invariably in the site of the hemodialysis catheter. Pulmonary embolism was observed in only one patient (Fig. 2). To our knowledge, only 11 cases of HIT in patients with vasculitis have been reported in literature (Table I). Detailed data are available for 7 patients (6 M and 1 F, median age 69.6 yo). Three patients had anti-PR3 antibodies, 2 anti-MPO antibodies, 1 both ANCA anti-MPO and anti-GBM antibodies (double positive), 1 only anti-GBM antibodies. Mean platelet count nadir was 45625/mm3 (range 17000-131000/mm3). Three out of 11 patients developed repeated clotting of the extracorporeal circuit and dialyzer, 2 patients had deep vein thrombosis in the site of the hemodialysis catheter, and one patient had also leukopenia and subarachnoid hemorrhage. Six patients were asymptomatic and developed only thrombocytopenia. Conclusion When patients with active systemic vasculitis develop venous thromboembolism and thrombocytopenia after exposure to heparin, or repeated coagulation of the extracorporeal circuit and dialyzer or plasma-filter, HIT should be included in the possible differential diagnosis, and Platelet factor 4–heparin antibody tests should be performed.

Clinical Management and Outcomes of Patients with Heparin/Platelet Factor 4 Antibodies: Retrospective Review at a Single Center.

Depending on the clinical setting, anti-platelet factor 4 (PF4)/heparin antibodies may be present in the absence of manifestations of heparin-induced thrombocytopenia (HIT), such as after bypass surgery. In addition, some patients have heparin-independent antibodies (ie, no inhibition of antibody binding in the ELISA with added heparin), but the clinical significance of a negative confirmatory result is unknown. Current recommendations for patients with HIT include treatment with a direct thrombin inhibitor (DTI) for up to 4 weeks. To assess current practice at a tertiary care center, we performed a retrospective analysis of patients with anti-PF4/heparin antibodies at Duke University Medical Center from January to July 2005, investigating diagnostic criteria, co-morbid conditions, therapeutic interventions, and outcomes. Anti-PF4/heparin antibody titers were determined by ELISA using a confirmatory step with excess heparin. A positive confirmatory result was defined as &gt;50% decrease in antibody binding in the presence of heparin. Of 59 patients with PF4/heparin antibodies, 50 had positive confirmatory results. For the confirm-positive patients, median platelet count nadir was 51,000±51,776/μL and % decrease from baseline was 71%±25%. Median peak PF4/heparin antibody titer was 0.9±0.8 AU. Seven patients were on the cardiology service, 15 were post-cardiac bypass surgery, 18 were on general medicine, and 4 were on general surgery. Sixteen patients (32%) had other potential causes for thrombocytopenia. Fifteen patients had thromboembolic events (TE); 12 had TE prior to the diagnosis of HIT (24%) and 3 patients sustained TE within 2 days of the positive test result. Twenty-six patients (52%) were treated with a DTI. Seven (of 21 evaluated) sustained bleeding complications requiring discontinuation of therapy. Six patients treated with a DTI died, 4 of whom had TE. Twenty-four patients were not treated with a DTI: 10 did not meet clinical criteria for HIT and 3 had bleeding complications that precluded DTI therapy. Of the remaining 11 patients not treated with a DTI, two died; one with sepsis, one with sepsis and stroke. One sustained DVT, but was therapeutic on warfarin at home when the positive ELISA result returned. Eight had no TE. Nine of the 59 patients had anti-PF4/heparin antibodies with a negative confirmatory test. Median platelet count nadir was 57,000±24,947/μL and % decrease from baseline was 62%±16%. Median peak PF4/heparin titer was 0.93±0.89 AU. Three patients were on the cardiology service, 1 was post-cardiac bypass surgery, 1 was on general surgery, and 4 were on general medicine. Eight patients had other causes for thrombocytopenia. Five patients sustained TE: one with lung cancer, one with clot on a central catheter, one with DIC and sepsis, and two with acute coronary syndromes at presentation. Only 1 patient with a negative confirmatory test was felt to have HIT, and that patient was treated with a DTI. One patient died with sepsis. In conclusion, anti-PF4/heparin antibodies are detected in diverse patient populations who frequently have additional risk factors for thrombocytopenia and thrombosis. Negative confirmatory results in the PF4/heparin ELISA were more frequently obtained in patients who did not meet clinical criteria for HIT. The decision to use a DTI in patients with anti-heparin PF4 antibodies must be individualized, since bleeding complications are frequent. Some patients with anti-heparin PF4 antibodies and no TE may not require treatment with a DTI, but this observation needs to be confirmed prospectively.

Transient Thrombocytopenia Produced by Administration of Macrophage Colony-Stimulating Factor: Investigations of the Mechanism

Administration of macrophage colony-stimulating factor (M-CSF) to mice (2 to 8 mg/kg/d × 5d) produced dose-dependent thrombocytopenia, which reached its nadir on days 4 to 5, followed by rapid recovery. Surprisingly, when administration of M-CSF was prolonged, the thrombocytopenia completely resolved, despite continued treatment. Splenectomy did not prevent the thrombocytopenia. Readministration of M-CSF after various intervals continued to produce the thrombocytopenic effect, even after 35 days. Measurements of Meg-CFC and megakaryocyte ploidy during the periods of M-CSF treatment and recovery of normal platelet levels showed no evidence of bone marrow suppression. Platelet survival was markedly decreased after 5 days of M-CSF (at the platelet count nadir) and after 9 days of continued M-CSF treatment, when the platelet count had returned to normal. Platelets from M-CSF–treated donors demonstrated normal survival when transfused into normal recipients. We concluded that thrombocytopenia produced by M-CSF was not due to suppression of thrombopoiesis, but to increased activity of the monocyte/macrophage system, which caused shortened platelet survival, and that subsequently, increased platelet production compensated for ongoing platelet destruction and resulted in normal platelet levels.

Transient Thrombocytopenia Produced by Administration of Macrophage Colony-Stimulating Factor: Investigations of the Mechanism

Administration of macrophage colony-stimulating factor (M-CSF) to mice (2 to 8 mg/kg/d × 5d) produced dose-dependent thrombocytopenia, which reached its nadir on days 4 to 5, followed by rapid recovery. Surprisingly, when administration of M-CSF was prolonged, the thrombocytopenia completely resolved, despite continued treatment. Splenectomy did not prevent the thrombocytopenia. Readministration of M-CSF after various intervals continued to produce the thrombocytopenic effect, even after 35 days. Measurements of Meg-CFC and megakaryocyte ploidy during the periods of M-CSF treatment and recovery of normal platelet levels showed no evidence of bone marrow suppression. Platelet survival was markedly decreased after 5 days of M-CSF (at the platelet count nadir) and after 9 days of continued M-CSF treatment, when the platelet count had returned to normal. Platelets from M-CSF–treated donors demonstrated normal survival when transfused into normal recipients. We concluded that thrombocytopenia produced by M-CSF was not due to suppression of thrombopoiesis, but to increased activity of the monocyte/macrophage system, which caused shortened platelet survival, and that subsequently, increased platelet production compensated for ongoing platelet destruction and resulted in normal platelet levels.

The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit

Thrombopoietin (c-Mpl ligand) has recently been purified and is considered to be the humoral regulator of platelet production. To see whether this molecule possessed the physiologic characteristics necessary to mediate the feed-back loop between blood platelets and the bone marrow megakaryocytes, we determined the relationship between blood levels of thrombopoietin and changes in the circulating platelet mass. We developed a model of nonimmune thrombocytopenia in rabbits by the subcutaneous administration of busulfan. Compared with pretreatment plasma, plasma taken from all thrombocytopenic rabbits at their platelet nadir contained increased amounts of thrombopoietin. All of this activity was neutralized by soluble c-Mpl receptor. We subsequently measured the level of thrombopoietin in the circulation over the entire time course after the administration of busulfan. As the platelet mass declined, levels of thrombopoietin increased inversely and proportionally and peaked during the platelet nadir. With return of the platelet mass toward normal, thrombopoietin levels decreased accordingly. When platelets were transfused into thrombocytopenic rabbits near the time of their platelet count nadir, the elevated levels of thrombopoietin decreased. In addition, platelets were observed to remove thrombopoietin from thrombocytopenic plasma in vitro. These results confirm that thrombopoietin is the humoral mediator of megakaryocytopoiesis and suggest that the platelet mass may directly play a role in regulating the circulating levels of this factor.

Thrombocytopenia caused by passive transfusion of anti-glycoprotein Ia/IIa alloantibody (anti-HPA-5b)

We describe a patient who developed transient and moderately severe thrombocytopenia (platelet count nadir 35 x 10(9)/L) after the transfusion of plasma. Using the technique of direct radioimmunoprecipitation, we showed that during the thrombocytopenia episode, the patient's platelets had IgG specifically bound to the glycoprotein (GP) Ia/IIa complex. Indirect radioimmunoprecipitation using serum from the plasma donor confirmed that anti-HPA-5b (anti- Zava) was the cause of GP Ia/IIa sensitization. The relatively mild thrombocytopenia, compared with passive alloimmune thrombocytopenia caused by anti-HPA-1a (anti-P1A1), may reflect the low copy number of HPA-5 compared with HPA-1. Direct radioimmunoprecipitation permits the detection of the GPs carrying the known platelet alloantigen systems, and this study suggests that this technique can be used to diagnose passive alloimmune thrombocytopenia.

Thrombocytopenia caused by passive transfusion of anti-glycoprotein Ia/IIa alloantibody (anti-HPA-5b)

We describe a patient who developed transient and moderately severe thrombocytopenia (platelet count nadir 35 x 10(9)/L) after the transfusion of plasma. Using the technique of direct radioimmunoprecipitation, we showed that during the thrombocytopenia episode, the patient's platelets had IgG specifically bound to the glycoprotein (GP) Ia/IIa complex. Indirect radioimmunoprecipitation using serum from the plasma donor confirmed that anti-HPA-5b (anti- Zava) was the cause of GP Ia/IIa sensitization. The relatively mild thrombocytopenia, compared with passive alloimmune thrombocytopenia caused by anti-HPA-1a (anti-P1A1), may reflect the low copy number of HPA-5 compared with HPA-1. Direct radioimmunoprecipitation permits the detection of the GPs carrying the known platelet alloantigen systems, and this study suggests that this technique can be used to diagnose passive alloimmune thrombocytopenia.