Risk Of Thrombotic Microangiopathy Research Articles

Clinical features of women with thrombotic microangiopathy in pregnancy: A case series from a single Japanese tertiary perinatal care center.

Although perinatal thrombotic microangiopathy has become increasingly understood, the racial characteristics of patients with this condition remain unclear. Herein, we report the characteristics of patients with perinatal thrombotic microangiopathy at a single institution in Japan. We conducted a retrospective study over a 5-year period from January 1, 2017, to December 31, 2021, using the electronic medical records of pregnant women who delivered at the perinatal center of our hospital. We extracted the data of those who developed perinatal thrombotic microangiopathy and evaluated their characteristics at the time of disease onset, final diagnosis, and maternal and fetal outcomes. Of the 10 224 deliveries that occurred during the 5-year period, only seven patients (0.06%) had perinatal thrombotic microangiopathy. The median pre-pregnant body mass index was 18.65 kg/m2 (minimum 17.3 kg/m2 , maximum 20.7 kg/m2 ). More than half of the patients were conceived by in-vitro fertilization, and 42% these had twin deliveries. Four patients had a history of rheumatic disease. The other three patients without underlying diseases developed thrombotic microangiopathy with HELLP syndrome, and one patient transitioned to atypical hemolytic uremic syndrome. Based on low body mass index and in-vitro fertilization, which are characteristic of Japanese women, medical complications and twin pregnancies may be a risk for thrombotic microangiopathy. Additionally, depending on the cause of thrombotic microangiopathy, its timing and onset differed.

Late Presentation of Carfilzomib Associated Thrombotic Microangiopathy.

Multiple Myeloma (MM) is a plasma cell disorder characterized by abnormal proliferation of plasma cells resulting in overproduction of paraprotein. Proteasome inhibitors (PI) have been a corner stone for the treatment of MM. Thrombotic Microangiopathy (TMA) is a recent hematological adverse event that has newly been recognized in multiple PI. TMA leads to end-organ damage and infarction by microthromobi. TMA pathophysiology is not well understood and has multiple etiologies. We present a case of PI-induced TMA, along with literature review of cases diagnosed from 2008–2018. Unique to our case is the onset of presentation, more than 24 months after initiating carfilzomib. Our case highlights the need for vigilant monitoring and the importance of clinical suspicion in patients at risk for TMA.

Recombinant Thrombomodulin for the Treatment of Transplantation-Associated Coagulopathy after Allogeneic Hematopoietic Stem Cell Transplantation

Background: Thrombotic microangiopathy (TMA) and sinusoidal obstruction syndrome (SOS) as well as acute GVHD are major complications after allogeneic hematopoietic stem cell transplantation (alloHSCT) to overcome to achieve better overall survival. These complications are closely relevant to inflammation and coagulation involving endothelium, which are named as transplantation-associated coagulopathy (TAC). Recombinant thrombomodulin (rTM) is a new drug for treating DIC approved by Japanese Ministry of Health, Labour and Welfare in 2008. Membranous TM has many aspects to inhibit inflammation via activated Protein C (APC), lectin-like domain, and activated thrombin-activatable fibrinolysis inhibitor as well as to inhibit coagulation by binding factor IXa and Xa through APC. Biomarkers such as inflammatory cytokines and endothelial molecules are expected to be clue in elucidating TAC. We established SIGHT study group to explore above complications following alloHSCT. In the present study, we investigated the effects of rTM on levels of the biomarkers and whether we could prevent TAC using rTM among registered patients in the SIGHT study group.Patients and methods: SIGHT study group covered nationwide institutes more than 70 in Japan. Patients whoever were eligible for alloHSCT to treat hematopoietic disorders by physicians decision were permitted and written informed consent was requested to register in the study. Blood samples were collected from the patients before and after transplantation through day 28. Levels of cytokines (IL-6, TNF-α, HMGB1, MCP-1, RANTES) and soluble molecules (VCAM-1, E-selectin, PAI-1, PDMP) were measured by ELISA. rTM was administered as a prophylactic therapy for TAC in day 4-14 after alloHSCT. Control group was received heparin or no anti-coagulation therapy as prophylaxis during same schedule as rTM group. Patients were not randomized to these three arms but allowed to select one by their physicians decision. The primary endpoint was a comparison of fluctuation of these biomarkers in three arms. Secondary endopoint was a comparison of the rate of developing TAC.Results: The subjects were 293 patients who underwent alloHSCT in SIGHT study group between June 2010 and February 2014. 271 patients out of them were analyzed to measure level of these biomarkers. There was no significant difference in all characteristics but GVHD prophylaxis between two groups. rTM group received more cyclosporine than control group (p=0.05). MCP-1 and IL-6 exhibited more significant elevations on day 7 after alloHSCT, while HMGB-1 did on the day of alloHSCT. In contrast, the levels of TNF-α, E-selectin, VCAM-1, PAI-1 and PDMP exhibited increment since around day 7 after alloHSCT. Significant improvements in TNF-α, E-selectin, VCAM-1, HMGB-1, PAI-1 and PDMP was shown after rTM-treatment, but not shown in control group. Regarding complications following alloHSCT, the rate of developing acute GVHD and SOS was significantly lower in rTM group than without it (36.5% vs 62.2%, p=0.000; 12.5% vs 24.5%, p=0.032, respectively), while TMA did not differ (8.4% vs 10.2%, p=0.961). Stepwise multivariate logistic regression analyses revealed that anti-coagulation therapy without rTM and the level of PAI-1 on day 28 after HSCT were independent risk factor for acute GVHD (p=0.000, odds ratio=3.006; p=0.000, odds ratio=1.068, respectively). Also anti-coagulation therapy without rTM and the level of HMGB-1 on day 28 after HSCT were significantly predictive for risk of SOS (p=0.015, odds ratio=2.650; p=0.001, odds ratio=1.433, respectively). Tacrolimus was significantly good risk of SOS (p=0.022, odds ratio=0.404). The level of VCAM-1 on day 28 after HSCT was significantly associated with risk of TMA (p=0.040, odds ratio=1.001).Conclusions: We identified predictive biomarkers for TAC following alloHSCT, which were PAI-1 for acute GVHD, HMGB-1 for SOS, and VCAM-1 for TMA, respectively in this study. The present findings suggest that rTM has the possibility to play a therapeutic role for acute GVHD and SOS induced by suppression on these biomarkers. Endothelial and pro-coagulant biomarkers were released delayed compared with inflammatory biomarkers. TMA is reported to develop around day 44 in median after alloHSCT. Further studies are needed whether rTM should administer later or longer to improve TMA than the present duration after alloHSCT. DisclosuresNo relevant conflicts of interest to declare.

The Role of Endothelial Cell Injury in Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) refers to a clinical and pathologic syndrome in which endothelial injury results in the manifestations of thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury. A host of causes may induce endothelial injury and TMA, including enteric bacterial toxins, deficiency or dysfunction of complement regulatory proteins, deficiency or inhibition of von Willebrand factor-cleaving proteases, and factors that inhibit endothelial cell proliferation and turnover. This has led specialists to concentrate on these specific inciting factors in terms of designing treatment and management. However, a key and less recognized factor is the underlying level of endothelial health. Many persons with hereditary causes may remain disease free for years or may never develop disease. Others with acute inciting events, such as Escherichia coli O157 enteritis, never manifest TMA. Experimental studies document the importance of specific factors, such as endothelial nitric oxide levels, in helping protect animals from TMA. This suggests that one might approach the management of TMA not simply with specific treatments aimed at the underlying hereditary cause or inciting event, but rather at general measures that may improve overall endothelial health. We propose studies to determine whether interventions that improve endothelial health, such as the administration of angiotensin-converting enzyme inhibitors, statins, vitamin C, allopurinol, or nitric oxide-producing drugs, may be able to prevent TMA, even in persons with underlying hereditary conditions that otherwise would predispose them to these diseases.

Heparin cofactor II as a predictor of thrombotic microangiopathy after bone marrow transplantation

The pathogenesis of thrombotic microangiopathy (TMA) after allogeneic bone marrow transplantation (BMT) remains unclear since ADAMTS13, which is implicated in primary thrombotic thrombocytopenic purpura (TTP), has been shown to have no role in this condition. We investigated whether the onset of TMA after BMT could be predicted by measuring heparin-cofactor II (HC II), a marker for thrombosis of unknown etiology. In 30 consecutive BMT patients, the serum HC II level was measured before conditioning and one week after recovery from leukopenia. Four of the 30 patients developed TMA, and 26 did not. Before conditioning, the mean serum HC II level was 1.748 ± 0.37 U/mL in the TMA group and 0.889 ± 0.25 U/mL, in the non-TMA group, being higher in the former group (p < 0.01, t-test). After recovery from leukopenia, the two groups showed no significant difference of serum HC II. The HC II level at the onset of TMA was above the upper limit of normal in only one out of four patients. These results suggest that vascular endothelial damage due to chemotherapy before BMT increases the risk of TMA, and that HC II is useful for predicting the occurrence of TMA after BMT.

Thrombotic microangiopathy after renal transplantation in the United States

Background: Analysis of the incidence, time to event, and risk factors for thrombotic microangiopathy (TMA) after renal transplantation (RT), has not been reported in a national population. Methods: This is a historical cohort study of 15,870 RT recipients in the United States Renal Data System (USRDS) with Medicare as their primary payer between January 1, 1998, and July 31, 2000, followed until December 31, 2000. Patients with Medicare claims with a diagnosis of TMA (International Classification of Diseases, 9th Revision, codes 283.11x or 446.6x) after RT were assessed by Cox regression. Results: Among patients with end-stage renal disease owing to hemolytic uremic syndrome (HUS), 29.2% later had TMA versus 0.8% of patients with ESRD owing to other causes. The incidence of TMA in RT recipients was 5.6 episodes per 1,000 person-years (PY; 189/1,000 PY; for recurrent TMA versus 4.9/1,000 PY for de novo TMA). The risk of TMA was highest for the first 3 months after transplant. Risk factors for de novo TMA included younger recipient age, older donor age, female recipient, and initial use of sirolimus. Patient survival rate after TMA was approximately 50% at 3 years. Conclusion: De novo TMA is uncommon and may occur later after RT than previously reported. Risk factors for de novo TMA were also identified.