[Effect of anticoagulant therapy on the course of COVID-19 in comorbid patients].

INTRODUCTION: Analysis of the pathogenesis of coronavirus infection caused SARS-CoV-2 indicates a significant impact of hemorheological disorders on its course and outcomes. It is known that chronic cardiovascular diseases are associated with the risk of severe course and lethal outcomes both in COVID-19 and other infectious diseases. Therefore, in each case it is necessary to study the interaction and mutual influence of different components of the treatment program prescribed to such patients.The purpose of this work was to evaluate the effect of coagulation activity on the course of a novel coronavirus infection (COVID-19) and to justify the management of comorbid patients having been received novel oral anticoagulants (NOACs) in previously selected doses according to indications in concomitant somatic diseases. MATERIAL AND METHODS: Total 76 cases of confirmed coronavirus infection in patients who had been received initial therapy on an outpatient basis were analyzed. 26 patients who received NOACs (rivaroxaban, apixaban, dabigatran) made up the main group and 50 - the comparison (control) group in which patients had not been administered any drugs that affect blood clotting until the episode of COVID-19. All patients have been prescribed therapy following the Provisional guidelines «Prevention, diagnosis and treatment of coronavirus infection (COVID-19)¼ (https://static-0.minzdrav.gov.ru/system/attachments/attaches/). RESULTS AND DISCUSSION: The number of hospitalizations was significantly fewer in the group of patients who had been received NOACs (19 vs. 66% in the control group). No deaths or cases of severe respiratory and/or renal failure were observed in the main group, while adverse outcomes were noted in 14% of patients who had not been administered these drugs. CONCLUSION: Taking NOACs reduces the probability of severe course and adverse outcomes in the development of coronavirus infection caused by SARS-CoV-2, which indicates a significant contribution of coagulation mechanisms to the pathogenesis in COVID-19. There were no indications for drug replacement and correction of anticoagulant therapy regimens in patients who received adequate therapy with oral anticoagulants for treating a non-severe form of coronavirus infection in ambulatory patient settings.

Successful treatment of amniotic fluid embolism complicated by disseminated intravascular coagulation with rivaroxaban: A case report.

RATIONALE: An amniotic fluid embolism (AFE) is a rare, lethal syndrome that is commonly associated with disseminated intravascular coagulation (DIC). Anticoagulation therapy is the most important strategy to inhibit excessive activation of the coagulation cascade in patients with AFE and DIC. At present, treatment of AFE with rivaroxaban has not been reported. PATIENT CONCERNS: We report a 37-year-old woman (gravida 2, para 1) at 39 weeks' gestation with irregular contractions of the uterus was admitted to the obstetrical department. Ten minutes after the spontaneous rupture of the membranes, the patient complained of dyspnea and dysphoria and exhibited cyanosis of her lips. The patient's blood pressure decreased and heart rate increased rapidly, and 2100 mL of unclotted blood flowed from her vagina within 1 hour. Her platelet count dropped to 21 × 10/L, and the results from routine coagulation tests, and D-dimer and fibrin degradation product tests were obviously abnormal. DIAGNOSES: According to the current research consensus, AFE with DIC should be considered immediately when sudden cardiovascular collapse occurs around the time of labor and delivery, followed by the development of coagulopathy and hemorrhage. INTERVENTIONS: In addition, the variety of supportive treatments, rivaroxaban was used in anticoagulant therapy. OUTCOMES: At follow-up 30 and 60 days, there were no complaints of discomfort or abnormal laboratory assays. The patient recovered completely. LESSONS: This case highlights that rivaroxaban, as a direct inhibitor of activated factor Xa, demonstrates a good therapeutic efficacy for treating AFE with DIC.

Tetrahydropalmatine has a therapeutic effect in a lipopolysaccharide-induced disseminated intravascular coagulation model.

OBJECTIVES: The aim of this study was to determine the therapeutic effects of tetrahydropalmatine (Tet) on disseminated intravascular coagulation (DIC) by exploring the role of Tet using a lipopolysaccharide (LPS)-induced DIC model. Methods/Materials: We established a mouse DIC model by injecting LPS. Hematoxylin-eosin (HE) staining was performed to detect liver and kidney damage. Blood samples were obtained to determine liver and kidney injury indexes, coagulation indexes, and inflammatory cytokines. An in vitro cell inflammation model was also established. Tumor necrosis factor-α (TNF-α) levels and nuclear factor kappa B (NF-κB) signaling pathway activation were determined by western blot. RESULT: Tet ameliorated the damage to organ tissues, improved coagulation indexes, and reduced the inflammatory cytokine production in LPS-induced mouse DIC. Tet also inhibited TNF-α expression by suppressing NF-κB signaling pathway activation in an in vitro LPS model using RAW 264.7 macrophages. CONCLUSIONS: Tet has a mitigating and therapeutic effect on the LPS-induced DIC model via anticoagulant and anti-inflammatory effects, showing its potential as an adjunct to DIC treatment.

Safety and effectiveness of a prothrombin complex concentrate in approved and off-label indications.

OBJECTIVE: To evaluate the effectiveness and safety of prothrombin complex concentrates (PCCs) in approved and off-label indications. BACKGROUND: PCCs are approved for the urgent reversal of vitamin K antagonists (VKAs). Data concerning the efficacy, safety and dosing for off-label indications are limited, but they are included in massive bleeding protocols. METHODS: This was a retrospective review of cases treated with four-factor PCCs (4F-PCCs) between January 2009 and 2016. Efficacy end-points include: (i) VKA reversal efficacy assessed by international normalised ratio (INR) normalisation (<1·5) and (ii) clinical efficacy as bleeding cessation and/or decreased number of transfused blood components and 24-h mortality in bleeding coagulopathy. The safety end-point is the incidence of thromboembolic events. RESULTS: A total of 328 patients were included (51·8% male, median age 78 years old). Indications were as follows: VKA reversal (66·6%), bleeding coagulopathy (30·5%) and direct anticoagulant (DOAC) reversal due to bleeding (2·5%). VKA reversal was effective in 97·1% of patients, and 76·5% demonstrated complete reversal (INR < 1·5); only 34·3% patients needed hemoderivatives. Prior to emergency procedures, PCCs achieved global responses in 83% of patients, with no bleeding complication during intervention. DOAC reversal was effective in 88·9% of patients. Bleeding cessation was associated with the dose administered (P = 0·002). In coagulopathy bleeding, haemorrhage cessation, established by the International Society of Thrombosis and Haemostais (ISTH) definition, occurred in 56·7% of massive bleeding events and in 42·5% of other coagulopathies; 24-h mortality was 30%, mainly related to active bleeding. Ten thrombotic episodes were observed (3·1%). CONCLUSION: 4F-PCC was effective as adjuvant treatment with an acceptable safety profile, not only for the emergent reversal of VKAs but also for refractory coagulopathy associated with major bleeding.

Genistein has the function of alleviating and treating disseminated intravascular coagulation caused by lipopolysaccharide.

Symptoms of disseminated intravascular coagulation (DIC) include thromboembolism, acute attrition bleeding and multiple organ failure. Genistein isolated from leguminous plants has been shown to be effective in oxidation resistance and tumor inhibition. The present study was designed to evaluate the therapeutic effects of genistein in DIC and preliminarily discuss the mechanisms regarding the anti-inflammatory and anticoagulant effect of genistein. Swiss mice were randomly divided into the following groups-(1) lipopolysaccharide (LPS), (2) genistein, (3) dimethyl sulfoxide (DMSO, the non-major solvent component of genistein), (4) DMSO + LPS, (5) saline control group, and (6) heparin control group. LPS was injected intraperitoneally in all the groups except the DMSO group and saline control group. Our results significantly showed that the morphological structure of the liver and kidneys was improved and the fiber protein deposition was decreased, with remarkable improvement of coagulation indicators, function indicators and inflammatory factors in the genistein treatment group compared with the LPS group. In vitro phosphorylated-nuclear factor kappa-light-chain-enhancer of activated B cells and interleukin-6 were obviously reduced in the genistein treatment group compared with the LPS group in RAW 264.7 murine macrophage cells. All the results suggested that genistein has the function of alleviating and treating LPS-induced DIC by anti-inflammatory and anticoagulation effects. We tentatively propose that genistein is a potential drug for auxiliary treatment of DIC.

The impact of oral arsenic and all-trans-retinoic acid on coagulopathy in acute promyelocytic leukemia.

The aim of our study was to evaluate the impact of oral arsenic (the realgar-indigo naturalis formula, RIF) and all-trans retinoic acid (ATRA) on coagulopathy in acute promyelocytic leukemia (APL) compared with intravenous arsenic trioxide (ATO) and ATRA during induction. Mitoxantrone was added to all the patients at a dose of 1.4mg/m2 per day for 5-7 days. D-dimer levels, prothrombin time (PT), fibrinogen (Fbg) levels and the platelet count were comparably analyzed among 83 newly diagnosed APL patients treated with RIF (n=45) or with ATO (n=38). Since induction therapy with RIF and ATRA, the median levels of Fbg, PT and platelets were recovered to the normal range within 4days, 10days and 28days, respectively. The last day of platelet and plasma transfusion was day 12 (range: 0-24 days) and day 3 (range: 0-27 days), respectively. Among the 42 patients with a disseminated intravascular coagulation (DIC) score=4, the consumption of transfused platelets was less in the RIF group than that in the ATO group (P=0.037). In the 17 patients with a DIC score <4, prompt recovery of Fbg levels (P=0.028) was observed in the RIF group compared with that in the ATO group (P=0.401). RIF and ATO showed similar effects on the recovery of coagulopathy in APL patients. RIF had a potential beneficial effect in accelerating the recovery of thrombocytopenia and hypofibrinogenemia for subclinical DIC patients.

Aortic Aneurysm-associated Disseminated Intravascular Coagulation that Responded Well to a Switch from Warfarin to Rivaroxaban.

We describe a case in which uncontrolled chronic disseminated intravascular coagulation (DIC) caused by an aortic aneurysm that was exacerbated by chemotherapy for lung cancer, showed dramatic improvement when warfarin, which was being administered for atrial fibrillation, was replaced by rivaroxaban, a direct oral anticoagulant (DOAC). The present case is interesting because a DOAC was effective in treating DIC due to an aortic aneurysm, whereas warfarin, another oral anticoagulant, was ineffective. In controlling DIC, it is important to inhibit activated coagulation factors such as thrombin and activated factor X, rather than the coagulation factors, which act as substrates.

[Meningococcal Septicemia Revealing Multiple Myeloma: A Case Report].

Meningococcal infection is among the most devastating diseases. It is rarely seen in Japan. However, several environmental and host factors have been associated with increased risks of Neisseria meningitidis infection. We present a case of invasive N. meningitidis infection that revealed the presence of multiple myeloma. A 55-year-old Japanese man was admitted with fever and altered consciousness. He was sent to the intensive care unit for septic shock and disseminated intravascular coagulation. In addition to standard septic shock and multiple organ failure treatment, polymyxin-B immobilized column direct hemoperfusion was performed. His blood culture was positive for N. meningitidis. The patient gradually improved and was discharged on day 35. We evaluated the risk factors for the development of meningococcal infection. A laboratory examination showed that the patient was negative for human immunodeficiency virus antibody and had a normal total complement function. However, his serum immunoglobulin G level was high, and serum and urine protein electrophoresis detected a monoclonal gammopathy. A bone marrow examination led to the diagnosis of multiple myeloma. Because N. meningitidis bacteria spreads between individuals in close contact through the exchange of oral secretions, droplet precautions and antimicrobial chemoprophylaxis (ciprofloxacin, 500 mg) were implemented to prevent the spread of the meningococcal infection. Sporadic meningococcal infection warrants an evaluation for immunodeficiency and the prevention of secondary infection.

Use of rivaroxaban for the effective management of disseminated intravascular coagulation associated with abdominal aortic aneurysm.

A 67-year-old man with non-valvular atrial fibrillation (AF) and previous myocardial and cerebral infarctions had uncontrollable bleeding after undergoing dental extraction because of an exacerbation of chronic disseminated intravascular coagulation (DIC) due to an abdominal aortic aneurysm. After successful treatment of the bleeding with the transfusion of fresh frozen plasma and platelets, nafamostat mesilate was used to treat the chronic DIC. Finally, rivaroxaban (an oral direct Factor Xa inhibitor) was prescribed for chronic DIC, as well as non-valvular AF. Following the initiation of rivaroxaban, the chronic DIC gradually improved, and the patient was discharged.

Effective treatment with para-aminomethylbenzoic acid for chronic disseminated intravascular coagulation associated with aortic dissection.

Chronic disseminated intravascular coagulation is a rare complication of aortic dissection. Surgical correction or low molecular weight heparin is treatment of choice, but for a severe bleeding problem due to excessive fibrinolysis, para-aminomethylbenzoic acid would be a simple and effective therapeutic approach.

Network pharmacology analyses of the antithrombotic pharmacological mechanism of Fufang Xueshuantong Capsule with experimental support using disseminated intravascular coagulation rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Xueshuantong (FXST) Capsule is developed on a traditional Chinese medicine remedy, with a four-herb formula of Panax notoginseng, Radix astragali, Salvia miltiorrhizae and Radix scrophulariaceae. It has been used for treatment of the clinic cardiovascular disease for many years. MATERIALS AND METHODS: Due to its complexity of compositions and polypharmacological effects, it often complicates understanding of the mechanisms of action. In the present work, we have constructed an integrated model of system pharmacology to investigate the polypharmacological mechanisms of FXST formulation for treatment of thrombosis disease. RESULTS: The predicted results showed that 22 ingredients in FXST were closely associated with 41 protein targets related to blood coagulation, fibrinolysis and platelet aggregation. Through analysis of the compound-protein target association, significant cross-targets between each herb indicated the multiple active chemical ingredients might interact with the same target simultaneously and thus explained the synergistic mechanisms of the principle of Traditional Chinese medicines (TCMs) as ''Jun (emperor) - Chen (minister) - Zuo (adjuvant) - Shi (courier)''. To validate the polypharmacological effects predicted by our network pharmacology (NetPharm) analysis, we have carried out experimental investigation the effects of FXST on the disorders of the blood coagulation system in a lipopolysaccharide-induced disseminated intravascular coagulation (DIC) rat model. The results showed that FXST could significantly ameliorate the activation of coagulation system, which is congruent with the cross-target prediction by NetPharm approach. CONCLUSIONS: The combined investigations provide more insight into better understanding of the pharmacological mechanisms of FXST, and may also offer an alternative avenue to further explore the chemical and pharmacological basis of TCMs.

Rivaroxaban for the treatment of consumptive coagulopathy associated with a vascular malformation.

The localized activation of coagulation in vascular malformations can lead to a consumptive coagulopathy characterized by elevated D-dimers and a consumption of fibrinogen and platelets, eventually giving rise to a bleeding tendency. By reducing coagulation activation, anticoagulant treatment with heparin is able to limit this haemostatic dysregulation and the associated bleeding diathesis. Here, we present a case of a consumptive coagulopathy due to a large venous malformation with a sustained correction of the fibrinogen depletion and associated bleeding tendency both with subcutaneous enoxaparin and with the oral factor Xa inhibitor rivaroxaban.

[Pharmacological therapies for ARDS].

Acute respiratory distress syndrome (ARDS) is a noncardiogenic pulmonary edema resulting from increased capillary permeability. Numerous pharmacologic therapies have been studied for prevention and treatment of ARDS. Although several pharmacological therapies could improve patient's respiratory function, there have been no controlled studies which clearly demonstrated the clinical benefit for ARDS-related mortality. The role of corticosteroids in ARDS remains controversial. Available evidence is against early administration of high-dose corticosteroids (methylprednisolon 120 mg x kg-1 x day - 1). In contrast, low-dose corticosteroid therapy (methylprednisolon 0.5-2.5mgg kg-1 xday-1)remains controversial. With regard to sivelestat sodium, a specific inhibitor of neutrophil elastase, although the effectiveness in decreasing mortality was not clarified, increases in lung oxygenation and ventilator-free days have consistently been revealed. Other probable pharmacologic therapies for ARDS include continuous infusion of cisatracurium. In conclusion, there are not established drugs for ARDS, and further studies are necessary to reveal the clinical effectiveness of the above mentioned and novel pharmacologic therapies.

Effects of enrofloxacin, flunixin meglumine and dexamethasone on disseminated intravascular coagulation, cytokine levels and adenosine deaminase activity in endotoxaemia in rats.

The aim of this study was to determine the effects of drugs used in the treatment of endotoxaemia on disseminated intravascular coagulation, cytokine levels and adenosine deaminase activities in endotoxaemic rats. Rats were divided into seven groups. Lipopolysaccharide (LPS) was injected into all groups, including the positive control group. The other six groups received the following drugs: enrofloxacin (ENR), flunixin meglumine (FM), low-dose dexamethasone (DEX), high-dose DEX, ENR + FM + low-dose DEX, and ENR + FM + high-dose DEX. After the treatments, serum and plasma samples were collected at 0, 1, 2, 4, 6, 8, 12, 24 and 48 hours (h). A coagulometer was used to determine the levels of coagulation values, while ELISA was used to assay serum cytokines and adenosine deaminase (ADA). Low-dose DEX alone and combined treatments depressed the levels of cytokines and ADA (from 371 to 70 IU/L at 6 h) significantly and inhibited the decrease of coagulation values (antithrombin from 67 to 140% at 6 h, fibrinogen from 54 to 252 mg/dL at 6 h). In summary, FM + high-dose DEX may be the preferred treatment of endotoxaemia because of its highest effectiveness. FM plus high-dose DEX may be a new therapy for endotoxaemic domestic animals.

Vinorelbine plus 24-hour infusion of high-dose 5-fluorouracil and leucovorin as effective palliative chemotherapy for breast cancer patients with acute disseminated intravascular coagulation.

BACKGROUND: Cancer-related acute disseminated intravascular coagulation (DIC) is uncommon, but it is a severe complication resulting in a very dismal prognosis. Choosing the appropriate chemotherapy agents to treat the underlying cancer and stop the acute DIC process effectively, while avoiding chemotherapy-induced myelosuppression which may contribute to bleeding-related mortality, is difficult. Acute DIC in breast cancer is a rare condition and is not well studied. Therefore, we designed this study to determine the clinical characteristics and effective treatment for breast cancer patients with acute DIC. PATIENTS AND METHODS: From March 1996 to November 2008, patients with histologically proven breast cancer who presented with acute DIC at National Taiwan University Hospital were retrospectively analyzed. RESULTS: Sixteen patients were included in the study. Thirteen patients with breast cancer-related acute DIC were treated with various kinds of chemotherapy, one with tamoxifen, and two with supportive care only. Four patients responded to treatment; three of the responders received vinorelbine with high-dose 5-fluorouracil and leucovorin (HDFL), the other received vinorelbine with cisplatin. The median survival of the responders and non-responders was 13 months and 0.5 month (p<0.001). There were no grade 3 or 4 hematologic or non-hematologic toxicities in the patients receiving vinorelbine-HDFL. CONCLUSION: Vinorelbine plus HDFL is considered a safe and effective palliative treatment of choice for breast cancer patients with acute DIC. Further prospective study is warranted.

Weekly 24-hour infusional 5-fluorouracil as initial treatment for advanced gastric cancer with acute disseminated intravascular coagulation.

BACKGROUND: Acute disseminated intravascular coagulation (DIC) occurring in patients with advanced gastric cancer (AGC) is a rare entity with a dismal prognosis. Conventional cytotoxic chemotherapy is usually not possible. Preliminary reports have suggested that non-myelosuppressive weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (HDFL) may be helpful. PATIENTS AND METHODS: Between 1994 and 2005, AGC patients who presented with acute DIC and were initially treated with HDFL (5-FU 2600 mg/m2 plus leucovorin 300 mg/m2, 24-h infusion weekly) were reviewed. RESULTS: Nineteen such patients were identified. After treatment with HDFL for a median of 4 weeks, 14 patients showed a response of the acute DIC. Eight of them subsequently received HDFL-based combination chemotherapy. The median survivals for the whole group, the DIC responders, and the 8 patients receiving subsequent combination chemotherapy were 3, 6, and 8 months, respectively. CONCLUSION: HDFL, as a safe initial treatment for AGC patients with acute DIC, provides the opportunity for further aggressive chemotherapy.

Effect of 1,25-dihydroxy-vitamin D3 in experimental sepsis.

BACKGROUND: In addition to the regulation of calcium homeostasis, vitamin D affects the cellular immune system, targets the TNF-alpha pathway and increases vasoconstrictor response to angiotensin II. We therefore examined the effect of 1,25-dihydroxy-vitamin D(3) on coagulation and organ failure in experimental sepsis in the rat. METHODS: Three series of placebo-controlled studies were conducted. All rats were pre-treated with daily SC injections of 1,25-dihydroxy-vitamin D(3) 100 ng/kg or placebo vehicle for 3 days. In study 1, sepsis was accomplished by abdominal surgery comprising a coecal ligation and puncture with a 1,2 mm needle, or sham surgery. In study 2, the rats had a single IP injection of lipopolysaccharide from E. Coli 0111:B4 (LPS) 8 mg/kg, or placebo. In study 3, an hour-long IV infusion of LPS 7 mg/kg, or placebo was given. RESULTS: All three models of sepsis showed significant effects on coagulation and liver function with reduced thrombocyte count and prothrombin time together with elevated ALT and bilirubin (p<0.05) as compared to controls. In study 1, the vitamin D treated rats maintained normal platelet count, whereas the vehicle treated rats showed a significant reduction (p<0.05). This effect of vitamin D on platelets was not found in the LPS-treated groups. We found no significant differences between vitamin D and placebo-treated rats with regards to liver function. CONCLUSION: The present data suggest a positive modulating effect of 1,25-dihydroxy-vitamin D(3) supplementation on sepsis-induced coagulation disturbances in the coecal ligation and puncture model. No such effect was found in LPS-induced sepsis.

[A case of advanced gastric cancer with simultaneous multiple bone metastases and double occurrence of disseminated intravascular coagulation successfully controlled with combined chemotherapy].

A 41-year-old man was found to have advanced gastric cancer with simultaneous multiple bone metastases when pyloric stenosis was being diagnosed in our hospital. We performed gastrojejunostomy from the lower third of the stomach to the upper third of the duodenum to relieve the obstruction. However, at 8 days after surgery, disseminated intra-vascular coagulation (DIC) occurred. Therefore, the patient was administered combined chemotherapy with TS-1 plus low-dose cisplatin in addition to anti-DIC therapy. TS-1 (150 mg/day) and cisplatin (10 mg/body intravenously over the course of 30 minutes) were administered on days 1 to 5, 8 to 12, and 15 to 19 (weekday-on/weekend-off schedule). There was remarkable response to this chemotherapy, and the patient was shifted from inpatient to outpatient treatment. The treatment course was repeated for 4 cycles until remission was observed. Because of hematologic relapse due to DIC at 6 months after the first treatment, he was readmitted for administration of combined chemotherapy. Fortunately, DIC once again responded to the same chemotherapy regimen. In this pathologic condition, combined chemotherapy is unavoidable when DIC occurs with cancer. Accordingly, it is necessary that an effective combined chemotherapy with mild bone marrow suppression be chosen. A companion drug should be chosen in consideration of delayed homo-toxicity and of the possibility of relapse into DIC in the drug withdrawal period. In addition, it is indispensable that careful consideration be given to the most favorable dose and regimen.

[Clinical observation on treatment of snake bite induced disseminated intravascular coagulation by qinwen baidu decoction].

OBJECTIVE: To observe the effect of Qinwen Baidu Decoction (QBD) in treating snake bite induced dissseminated intravascular coagulation (DIC). METHODS: Forty-six patients were randomly divided into the control group (n = 16) and the treated group (n = 30). They were all treated with the conventional therapy, including application of anti-snake venom serum and supplement of blood agglutination factors. For the treated group, QBD was administered additionally. The efficacy of treatment, chief indexes for DIC (platelet, fibrinogen and prothrombin time) and their recovery time, etc. were observed. RESULTS: The total effective rate of the treated group was 93.33%, which was higher than that of the control group (56.35%), and the recovery time of chief DIC indexes in the treated group was significantly shorter than that in the control group respectively (P < 0.01). CONCLUSION: QBD shows obvious effects of shortening therapeutic course and enhancing efficacy in treating snake bite induced DIC.