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In 2020, infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) rapidly spread across the world to become a global pandemic. Coronavirus disease-2019 (COVID-19) is associated with a high rate of coagulopathy and thrombotic complications. The underlying mechanisms involved in these processes are complex. In addition to the low physical activity, blood coagulation activation accompanied by excessive immune/inflammatory reactions and vascular endothelialitis associated with the presence of intracellular SARS-CoV-2 and disrupted cell membranes contribute substantially to the complexity of the mechanisms. The types of thrombosis that occur include arterial thrombosis and venous thromboembolism. Microthrombi in alveolar capillaries are observed in COVID-19 patients. Considering the possible involvement of thrombosis in the worsening of COVID-19, prophylactic anticoagulant therapy, such as low-molecular-weight heparin or unfractionated heparin, is essential for patients with moderate and severe infections. Even with prophylactic anticoagulant therapy, the incidence of thrombosis remains high. Consequently, control of the underlying inflammation and vascular endothelial protection may be required in combination with anticoagulant therapy.

Despite the introduction of direct oral anticoagulants (DOAC), the need for more effective and safer antithrombotic strategies exists. Recently, the findings stating that the contact system is important for thrombus formation has identified factor XI as a potential target for new anticoagulants. Approximately 20-30% of patients who develop venous thromboembolism (VTE) also have cancer. To date, the drugs primarily used in the treatment of VTE are heparin in the acute phase and warfarin in the chronic phase. Recently, a large-scale international clinical trial, which examined the composite outcomes of VTE recurrence and major bleeding in cancer patients, found that edoxaban, a direct factor Xa inhibitor, is not inferior to low-molecular-weight heparin. The study also showed that DOACs have a promising potential to prove therapeutically effective in future studies. Anticoagulants are associated with a severe side effect, bleeding, which makes emergency neutralization an important concern. Four-factor prothrombin complex concentrate can be used to reverse the effect of warfarin and could also be effective as a neutralizing agent in patients having received DOACs. Moreover, more specific reversing agents include the approved human monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran.

Inherited thrombophilia is a thrombotic diathesis caused by a variety of genetic abnormalities in anticoagulant factors such as antithrombin (AT), protein C (PC), and protein S (PS), or coagulation factors such as prothrombin and factor V. Patients with inherited thrombophilia often present with unusual clinical episodes of venous thromboembolism (VTE), which manifests as deep vein thrombosis or pulmonary thromboembolism in young persons (younger than 40 years), often with a positive family history of thrombosis. Moreover, the thrombosis sometimes recurs, despite anticoagulant therapy. The genetic background is known to differ between Caucasians and East Asians. Starting this April, inherited thrombophilia, AT, PC, or PS deficiency, are officially designated as intractable diseases, and the treatment of these diseases is subsidized as public expense.

"Microangiopathic hemolytic anemia (MAHA)" is now used to designate any hemolytic anemia related to RBC fragmentation, occurring in association with small vessel disease. In DIC, RBC fragmentation is thought to result from the deposition of fibrin or platelets within the microvasculature. The term "thrombotic microangiopathy (TMA)" is also used to describe syndromes characterized by MAHA, thrombocytopenia, and thrombotic lesions in small blood vessels. The most prominent diagnoses associated with TMA are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Many different disorders, including preeclampsia, infections, adverse drug reactions, hematopoietic stem cell transplantation, autoimmune diseases, and malignancies, can cause TMA (i.e., secondary TMA). Recently, because the pathogeneses of TTP and HUS have been elucidated, great progress has been made in diagnosis and treatments. However, the pathogenesis of secondary TMA remains unclear. Clinical problems awaiting solution in TMA management include determination of the positioning of rituximab in the treatment sequence of primary TTP, management of Shiga-toxin producing Escherichia coli-HUS complicated by encephalopathy, confirmation of the efficacy and long-term safety of eculizumab in the treatment of atypical HUS, and elucidating the pathogenesis of secondary TMA as well as improving the efficacy of treatment.

Congenital factor VII (FVII) deficiency is a bleeding disorder that requires optimal hemostatic management for each case due to its wide variety of bleeding symptoms. We experienced a patient with inherited FVII deficiency who demonstrated different FVII activities depending on tissue thromboplastins used for assays. An 82-year-old woman without any episodes of abnormal bleeding was found to have different FVII activities of 1.4% and 32% when assayed using thromboplastins from rabbit brain and human placenta, respectively. DNA sequencing analysis revealed a homozygous missense mutation of G10828A (FVII Padua) that caused an amino acid substitution of Arg304 to Gln (R304Q). Carriers of 304Q alleles are usually clinically asymptomatic and do not require FVII replacement therapies even in cases of homozygotes. In case a prolonged prothrombin time or reduced FVII activity is detected, re-examination using thromboplastins of other sources can be helpful for preliminary diagnosis of R304Q, in order to prevent unnecessary FVII replacement therapies.

We investigated a 56-year-old Japanese man with protein C deficiency, who was referred to our hospital because of venous sinus thrombosis and pulmonary thromboembolism. Protein C (PC) activity and the corresponding antigen level in plasma were 66% and 106% of the normal values, respectively. Both the activity and antigen levels of protein C were reduced by approximately 50% in plasma from the patient's mother. All exons and their flanking intron regions were amplified by PCR from genomic DNA. Sequencing analysis of the PCR fragments revealed that the patient was heterozygous for a C to T substitution at nucleotide position 6218, resulting in a single amino acid substitution of arginine (CGG) by tryptophan (TGG) at codon 169 of the heavy chain. We analyzed the patient, his mother, and normal controls by a Sac II digestion study of exon 7 and found that the patient and his mother had the same C to T point mutation at base 6218. This mutation could have been responsible for the defective activation of the molecule and the resulting thrombotic disorder. The patient is now being treated with warfarin, and so far no further clinical thrombotic episode has occurred.

It is well known that the administration of high-dose gamma-globulin concentrate is effective in alleviating thrombocytopenia in patients with idiopathic thrombocytopenic purpura (ITP). However, treatment can sometimes induce aseptic meningitis. A 25-year-old Japanese woman with antiphospholipid syndrome and ITP was conditioned with high-dose gamma-globulin concentrate prior to splenectomy. Three days after the initial gamma-globulin course, she experienced severe headache, vomiting, and high-grade fever. Cerebrospinal fluid examination yielded a diagnosis of aseptic meningitis. The patient's clinical symptoms and abnormal cerebrospinal fluid findings disappeared immediately after the discontinuation of gamma-globulin therapy. Cases of aseptic meningitis induced by high-dose gamma-globulin therapy are uncommon in the literature, and most involve children. Moreover, to our knowledge, only 1 Japanese adult ITP case of gamma-globulin-induced aseptic meningitis has been reported to date. Aseptic meningitis may be one of the important adverse effects of the administration of high-dose gamma-globulin concentrate to pediatric as well as adult ITP patients.

We measured plasma levels of tissue factor (TF), total tissue factor pathway inhibitor (TFPI) and free TFPI antigen in patients with diabetes mellitus (DM), hyperlipidemia and disseminated intravascular coagulation (DIC). The mean TF, total TFPI and free TFPI antigen concentrations were significantly higher in patients with DM than in controls and the plasma TF concentration was significantly higher in patients with retinopathy or nephropathy than in DM with no complications. The mean TF, total TFPI and free TFPI antigen concentrations were significantly higher in patients with hyperlipidemia than in controls. There was a significant positive correlation between levels of total TFPI and total cholesterol. In patients with hyperlipidemia, the level of total TFPI was significantly decreased compared to base line level by cholesterol lowering drug, however, free TFPI concentration did not change by cholesterol lowering drug. The TF and total TFPI concentrations were significantly higher in patients with DIC than in controls.