Recent Advances in Anticoagulant Treatment of Immune Thrombosis: A Focus on Direct Oral Anticoagulants in Heparin-Induced Thrombocytopenia and Anti-Phospholipid Syndrome

For more than 10 years, direct oral anticoagulants (DOACs) have been increasingly prescribed for the prevention and treatment of thrombotic events. However, their use in immunothrombotic disorders, namely heparin-induced thrombocytopenia (HIT) and antiphospholipid syndrome (APS), is still under investigation. The prothrombotic state resulting from the autoimmune mechanism, multicellular activation, and platelet count decrease, constitutes similarities between HIT and APS. Moreover, they both share the complexity of the biological diagnosis. Current treatment of HIT firstly relies on parenteral non-heparin therapies, but DOACs have been included in American and French guidelines for a few years, providing the advantage of limiting the need for treatment monitoring. In APS, vitamin K antagonists are conversely the main treatment (+/- anti-platelet agents), and the use of DOACs is either subject to precautionary recommendations or is not recommended in severe APS. While some randomized controlled trials have been conducted regarding the use of DOACs in APS, only retrospective studies have examined HIT. In addition, vaccine-induced immune thrombotic thrombocytopenia (VITT) is now a part of immunothrombotic disorders, and guidelines have been created concerning an anticoagulant strategy in this case. This literature review aims to summarize available data on HIT, APS, and VITT treatments and define the use of DOACs in therapeutic strategies.

Risk Factors in Cancer Patients

Numerous studies in recent years have proven that the oncological process is an independent risk factor for thrombosis. For a long period of time and at the moment, research is continuing on the pathogenesis of a prothrombotic state in cancer patients. It was shown that the degree of risk is influenced by such indicators as the histological type of tumor, the stage of development of the disease, surgery, duration and type of anesthesia, chemotherapy, hormonal therapy, age, the presence of central venous catheters, immobilization, thrombophilia, history of thrombosis, infections. Thrombosis in cancer patients is triggered by thrombogenic factors associated with the tumor, patient-associated factors and environmental factors. The tumor cell affects the balance of hemostasis by releasing procoagulant substances, profibrinolytic, proproteolytic and proaggregant activity, expression of adhesion molecules, secretion of proinflammatory and proangiogenic cytokines; new participants in the process have also been identified. Studies have confirmed the fact that inflammation and thrombosis are inextricably linked with each other and play an important role in the progression of the disease and metastasis. All this opens up new horizons for the development of modern innovative strategies for treating cancer patients and increasing survival.

Von Willebrand Factor Expression in Endothelium in a Co-Culturing System of Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is the most common cause of cancer and death from cancer among children, with an incidence of 1 in 1,750 children. A previous Dutch cohort study highlighted that 7.6% of children with ALL also developed venous thromboembolism (VTE; n=55/778). VTE increases the risk of morbidity and mortality in cancer patients. However, the mechanisms of hemostatic abnormality in ALL is not well understood. Von Willebrand factor (vWF) is involved in thrombosis and is a well-established marker for endothelial dysfunction. High vWF levels and qualitative abnormality of the protein have been documented in patients with ALL and may contribute to the prothrombotic state observed in these patients. Objective: To determine whether co-culturing cancerous ALL cells with healthy human umbilical vein endothelial cells (HUVECs) may increase vWF secretion from endothelial cells. Methods: HUVECs were obtained from Lonza Bioscience Solutions (Basel, Switzerland) and leukemic B-lymphoblasts (ALL cells) derived from bone marrow were obtained from ATCC (Manassas, Virginia, USA). Passages 3 to 5 were used in this study and cell lines were grown as per manufacturer's instruction. A confluent monolayer of HUVECs was established before the co-culturing experiments. Firstly, ALL cells and HUVECs were grown together (co-cultured) at a 1:1 ratio. Then, the conditioned media and cell lysates were harvested at three different time points and the vWF levels were quantitated by a vWF-ELISA. To further evaluate the effect of leukemic cells on the endothelium, ALL cells were also co-cultured at a 10:1 ratio to endothelial cells. All experiments were conducted in biological triplicates. Results: Cells were monitored throughout the study period and no morphological changes to the endothelial cells were observed. An accumulation of vWF was recorded over time in both the conditioned media and cell lysates. The differences in vWF levels between the co-culture group and HUVEC-only group at three time points (24, 48 and 72 hours) were not statistically significant. In addition, 10-fold differences in ratio between leukemic and endothelial cells did not have a meaningful effect on vWF levels. Discussions: In an in vitro co-culture system, ALL cells do not appear to induce an increase vWF secretion in HUVECs. Contrary to prior evidence, this study suggests that increased vWF secretion from endothelial cells may not be a contributor to the prothrombotic state observed in ALL. The circulating lymphoblasts may have a more pronounced effect on other endothelial layers where vWFs are highly expressed such as the pulmonary endothelium. On the other hand, peripheral blood pediatric leukemic lymphoblasts have been demonstrated to produce hemostatic factors, which may contribute the hemostatic imbalance in the progression of disease. In addition, the pathogenesis of thrombosis in ALL is likely to be therapeutically related since thrombosis rarely occurs at presentation. Alternative mechanisms, such as ADAMST13 and hemostatic factors' level and function or the use of chemotherapeutic agents, ought to be explored. Figure 1 Figure 1. Disclosures Matino: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Spark: Other: research grants; Octopharma: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: personal fees.

P.077 Mixed autoimmune hemolytic anemia: an unusual cause of ischemic stroke and extensive cerebral microbleeds

Background: Mixed autoimmune hemolytic anemia (mAIHA) is a rare autoimmune disorder that results in hemolysis with thrombotic complications like ischemic stroke. This is the first case report of cerebral microbleeds secondary to mAIHA. Methods: A literature review of mAIHA and cerebral microbleeds was conducted using the PubMed and Ovid MEDLINE databases from 1980 to 2021. Results: A 76 year old male with congenital deafness and rheumatoid arthritis presented with diffuse livedo reticularis and abdominal pain. He had fulminant hemolysis with new neurologic deficits and altered mental status. CT/CTA of the head and neck were unremarkable. MR brain revealed extensive cerebral microbleeds and multi-territory ischemic strokes. He was diagnosed with mAIHA, started on pulse methylprednisolone, and had no further microbleeds on follow-up MRI. From his clinical picture, common causes of cerebral microbleeds were ruled out such as cerebral amyloid angiopathy and hypertension. The pathogenesis of his microbleeds may be from concomitant severe hypoxia or a prothrombotic state, both previously reported in the literature. Conclusions: This is the first case report of extensive cerebral microbleeds secondary to mAIHA. When a patient develops acute neurologic deficits in the context of mAIHA, extensive cerebral microbleeds may be present possibly due to concomitant severe hypoxia versus a prothrombotic state.

Spontaneous regression of a thrombosed cerebral arteriovenous malformation in a patient with a prothrombotic state associated with multiple myeloma: A case report and literature review

Background: Cerebral arteriovenous malformations (AVMs) are pathologic communications between veins and arteries of the brain vasculature. Its spontaneous regression is rare, and many factors have been described in the effort to explain this phenomenon, including a hypercoagulable state. Case Description: We present the case of a spontaneous unruptured AVM regression in a patient where thrombosis of the malformation was found, probably due to a prothrombotic state associated with multiple myeloma (MM). Conclusion: We aim to contribute to the study of this rare phenomenon, presenting the relationship between a hypercoagulable state caused by MM and the spontaneous AVM regression that has not been previously reported.

Prevalence, Risk Factors, and Management of Stroke in Patients with COVID-19 Infection: A Review

In the current pandemic, it is imperative to comprehend and advance a search forward to explore the pathogenesis of stroke in COVID-19 infected patients. In this review, we have discussed the prevalence of stroke in COVID-19 infected patients and different risk factors associated with the stroke in COVID-19. We also presented a comprehensive review on management of Stroke Patients during the COVID-19 pandemic. The COVID-19 positive patients with stroke should be treated in a designated COVID-19 health care center as per the guidelines. Study also showed that older patients with a history of cardiovascular diseases, prothrombotic state, smoking, and infection significantly had a higher likelihood of stroke incidence. The study revealed that effective treatment of COVID-19 and reduction of the inflammatory conditions may seem to be the way forward to minimize the symptomatic stroke associated with COVID-19 infection, and rehabilitation of Stroke patients should be optimal during a pandemic.

COVID-19, cardiovascular diseases and cardiac troponins

There has been strong evidence of myocardial injury in coronavirus disease 2019 (COVID-19) patients with significantly elevated serum cardiac troponin (cTn). While the exact mechanism of injury is unclear, possible suggested pathological mechanisms of injury are discussed. These include increased susceptibility of the myocardium and endothelium to viral invasion, underlying hyperinflammatory state and subsequent cytokine storm, a hypercoagulable and prothrombotic state, and indirect myocardial injury due to hypoxemia. As a result of these pathological mechanisms in COVID-19 patients, cTn may be elevated largely due to myocarditis, microangiopathy or myocardial infarction. The utility of cTn as a biomarker for measuring myocardial injury in these patients and assessing its ability as a prognostic factor for clinical outcome is also discussed.

Prothrombotic state in patients with stable COPD: an observational study

BackgroundCOPD patients have an increased risk of cardiovascular disease and venous thromboembolism.MethodsThis study aimed to investigate whether patients with stable COPD have a prothrombotic state compared to COPD-free smokers. We conducted an observational study comparing levels of: D-dimers, INR, aPTT, coagulation factors: fibrinogen, FII, FV, FVII, FVIII, FIX, FX and coagulation inhibitors: protein S, proteins C and antithrombin between stable COPD patients and control subjects.ResultsA total of 103 COPD patients and 42 controls with similar age, sex, current smoking status, comorbidity burden and cardiovascular risk met the inclusion criteria. Compared to controls, COPD patients had higher levels of: D-dimers [360 (230–600) ng·mL−1versus 240 (180–400) ng·mL−1, p=0.001], fibrinogen (399±82 mg·dL−1versus 346±65 mg·dL−1, p<0.001), FII (122±22% versus 109±19%, p=0.004), FV (131±25% versus 121±19%, p=0.015), FVIII (143±32% versus 122±20%, p<0.001), FX [111 (94–134)% versus 98 (88–107)%, p=0.002] and lower levels of: Protein S [95 (85–105)% versus 116 (98–121)%, p<0.001], and antithrombin (94.4±11.5% versus 102.3±13.2%, p=0.001). In the COPD group, patients with more severe airflow limitation and frequent exacerbations had significantly higher levels of FII, FV and FX, whereas patients with higher CAT score had significantly higher levels of FX and lower levels of protein S.ConclusionPatients with stable COPD exhibited increased levels of key coagulation factors and decreased levels of coagulation inhibitors, namely protein S and antithrombin, compared to COPD-free smokers. Among COPD patients, increased levels of FII, FV and FX and decreased levels of protein S were found in patients with more severe disease.