Objective-Direct oral anticoagulants (DOAC) are replacing vitamin K antagonists (VKA) for the prevention of ischemic stroke and venous thromboembolism. We set out to assess the effect of prior treatment with DOAC and VKA in patients with aneurysmal subarachnoid hemorrhage (SAH). Methods-Consecutive SAH patients treated at two (Aachen, Germany and Helsinki, Finland) university hospitals were considered for inclusion. To assess the association between anticoagulant treatments on SAH severity measure by modified Fisher grading (mFisher) and outcome as measured by the Glasgow outcome scale (GOS, 6 months), DOAC- and VKA-treated patients were compared against age- and sex-matched SAH controls without anticoagulants. Results-During the inclusion timeframes, 964 SAH patients were treated in both centers. At the time point of aneurysm rupture, nine patients (0.93%) were on DOAC treatment, and 15 (1.6%) patients were on VKA. These were matched to 34 and 55 SAH age- and sex-matched controls, re-spectively. Overall, 55.6% of DOAC-treated patients suffered poor-grade (WFNS4-5) SAH compared to 38.2% among their respective controls (p = 0.35); 53.3% of patients on VKA suffered poor-grade SAH compared to 36.4% in their respective controls (p = 0.23). Neither treatment with DOAC (aOR 2.70, 95%CI 0.30 to 24.23; p = 0.38), nor VKA (aOR 2.78, 95%CI 0.63 to 12.23; p = 0.18) were inde-pendently associated with unfavorable outcome (GOS1-3) after 12 months. Conclusions-Iatrogenic coagulopathy caused by DOAC or VKA was not associated with more severe radiological or clinical subarachnoid hemorrhage or worse clinical outcome in hospitalized SAH patients.

Vitamin K antagonists (VKA) are recommended in patients with mechanical heart valves. Major bleeding events remain the most life-threatening complication of this therapy and sometimes it can occur in unusual anatomic areas. Spontaneous retroperitoneal hematoma is one of the rare complications of anticoagulation therapy, which needs to be recognized early and managed promptly. Here, we report a case of a 40-year-old woman with mechanical heart valve treated with acenocoumarol, who was admitted to the emergency department with abdominal pain and whose investigations came back in favor of a massive retroperitoneal hematoma. The patient was successfully treated through conservative management resulting in a good outcome. Clinicians should be careful when prescribing VKA and should always think of retroperitoneal bleeding in the event of abdominal pain or a sudden decrease in the hemoglobin levels of anticoagulated patients.

BACKGROUND: Spontaneous spinal epidural hematoma (SSEH) is a rare finding, but one with serious clinical implications. Oral anticoagulant drugs are known to be associated with the SSEH onset, particularly when combined with drugs increasing the bleeding risk.
METHODS: We present the case of a 62-year-old female on acencoumarol for her atrial fibrillation complicating severe mitral stenosis with a history of Ketoprofen use for the onset of her first symptoms. She presented to our emergency room with paraplegia and sphincter disturbance. Spinal magnetic resonance imaging (MRI) revealed a posterior SSEH extended from T10 to T12 requiring an urgent decompression of the spinal cord by laminectomy performed within 48 hours from the symptom\'s onset. After 3 months of rehabilitation, the patient improves partially her muscular strength with mostly unchanged sensitive and sphincteric levels.
UNASSIGNED: Vitamin K antagonists (VKA) use appears to be a high suspicion index for SSEH diagnosis resulting in earlier surgery and improving neurological outcome. Also, it is important to pay attention to the concomitant use of VKA and non-steroidal anti-inflammatory drugs which increase the risk of bleeding and may worsen the neurological outcome.
CONCLUSIONS: SSEH is a rare and serious finding which should be especially searched when a history of oral anticoagulation is reported in presence of neurological symptoms. A prompt and suitable management may improve the patient outcomes.

Here, the case of a 92-year-old female patient, who was diagnosed with atrial fibrillation and treated with phenprocoumon (Marcumar®), is reported. Pre-existing comorbidities were arterial hypertension, coronary heart disease, diabetes mellitus type 2, mild senile dementia and renal insufficiency. Despite treatment with phenprocoumon (Marcumar®), the patient experienced an ischaemic stroke. Her measured international normalized ratio (INR)-values during the months before the stroke were within the therapeutic range of 2-3, then suddenly decreased to 1.25. A retrospective inquiry failed to identify any significant changes in behaviour or therapy adherence, other than the consumption of 1.5 kg (3.3 lb) of hard-boiled candy liquorice in the days leading up to the stroke. The sudden decrease in INR-values may be explained by the influence of liquorice and its compounds on the pharmacokinetics of phenprocoumon (Marcumar®). In this context, the most important factors are the susceptibility of vitamin K antagonists to nutrition or metabolic irregularities, the influence of liquorice on the function of isoenzymes of the cytochrome P450 family that may lead to reduced bioavailability of phenprocoumon, and the influence of liquorice on peroxisome proliferator-activated receptor alpha transactivation.

Vitamin K antagonists (VKA) based oral anticoagulation, is widely used for the prevention and treatment of thromboembolic disease. The major complication of this therapy is bleeding, and sometimes it can occur in unsuspected areas. Spontaneous pectoral hematoma is one of the rare complications due to over anticoagulation by VKA therapy, with only a few cases reported in the literature. Concomitant use of this therapy with commonly used antibiotic, especially in the elderly with multiple comorbidities, can increase the risk of bleeding. Herein, we report a case of a 72-year-old woman under VKA for the treatment of atrial fibrillation, who presented with a spontaneous massive pectoral hematoma, while using antibiotic to treat a respiratory tract infection, who was successfully managed.

Primary immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenia, is defined by a reduced platelet count <50x109 and is clinically manifested through signs and symptoms such as bleeding, ecchymosis and petechiae. Its coexistence with the implantation of the mechanical valves and the necessity of anticoagulation creates an additional risk of bleeding. Although mechanical valves are indispensable in prolonging and improving the quality of life in patients with valvular heart disease, in the context of an additional bleeding risk factor, their presence could represent a threat to life exposing the patient to major complications and leading to death. The purpose of this case report is to discuss the disadvantages and possible fatal complications of the association between mechanical valves and severe thrombocytopenia. A possible solution to these downsides could be found in the future search in regenerative medicine and tissue engineering of heart valves resulting in products that do not require anticoagulation and do not pose a threat to patients with thrombocytopenia.

BACKGROUND: Specific immune-related adverse events in lung cancer treatment are rare and it is important that they are identified as they may have important adverse consequences. We report such a case here.
METHODS: A Caucasian female diagnosed with KRAS mutant advanced adenocarcinoma of the lung was enrolled in a phase Ib trial assessing the combination of an anti cytotoxic T-lymphocyte- associated protein 4 antibody and a programmed death-Ligand 1 inhibitor. For several years, she had also been taking warfarin for recurrent pulmonary embolism. At day 15 of treatment, she presented with grade 1 haematomas and signs of grade 2 hyperthyroidism. Blood tests revealed a normal number of platelets but an INR increased to 6.5. Thyroid function tests and auto antibodies confirmed the presence of an autoimmune thyroitidis. The study treatment was then stopped and the patient received 1mg/kg of prednisone and 40mg of propranolol. At day 28, the thyroid function and symptoms were normalized. No direct interactions exist between immunotherapy and vitamin K antagonists (VKA) but hyperthyroidism, through pharmacokinetic and metabolic mechanisms, can boost VKA plasma levels and increase INR, leading to hemorrhagic complications.
CONCLUSIONS: This case emphasizes that special consideration should be given to patients with VKA treatment planned to receive immunotherapy.

OBJECTIVE: In this pharmacovigilance study, we aimed to determine the incidence of spontaneously reported suspected adverse drug reactions (ADRs) related to oral anticoagulants: non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, rivaroxaban) and vitamin K antagonists (VKA) Research design and methods: In this retrospective observational study, we extracted all the individual case safety reports related to oral anticoagulants recorded in the Portuguese Pharmacovigilance Database (January 2010 to April 2015). The annual incidence of suspected ADRs was estimated using drug exposure data. Disproportionality of reporting ADR was addressed through reporting odds ratio (ROR) and 99% confidence intervals.
RESULTS: We appraised 794 suspected ADR (78% related to NOACs). The annual number of ADRs increased overtime with 9 ADRs/million Defined Daily Dose (DDD) at the end of 2014. The incidence of NOACs ADRs decreased from 2012 onwards. VKA showed a disproportion in \'Investigation\' (ROR 0.10, 99%CI 0.05-0.22) and \'Injury, poisoning and procedural complications\' (ROR 0.36, 99%CI 0.19-0.69) ADRs compared with NOACs. NOACs had a higher significant disproportion of \'Nervous system disorders\' related ADRs (ROR 3.98, 99%CI 1.50-10.53).
CONCLUSIONS: Reporting of ADRs associated with oral anticoagulants (mainly NOACs), is increasing. Exploratory disproportion analyses showed an increase of reports of nervous system ADRs with NOACs, and INR-related ADRs with VKA.

We report on a 81-year-old female admitted to the emergency department for the occurrence of abdominal pain after a minor trauma. She was on treatment with warfarin for atrial fibrillation. The abdominal computed tomography (CT) angiography revealed a retroperitoneal hematoma (RH) of the left iliopsoas muscle with no evidence of active bleeding. The international normalized ratio exceeded the upper recommended anticoagulation limit. Prothrombin complex concentrates (PCCs) were used for anticoagulation reversal. Two days later, the patient presented acute dyspnea and a pulmonary CT angiography showed an embolus in the right pulmonary artery. Enoxaparin was started. Thoracic symptoms improved and a second abdominal CT angiography revealed a reduction in RH. Apixaban was started from day 11. No further bleedings occurred and clinical conditions improved. Anticoagulation reversal with PCCs rapidly restores hemostasis, but, on the other side, the thrombotic risk due to their procoagulant effect should be considered.

BACKGROUND: Venous gangrene complicating deep vein thrombosis in the context of anticoagulation use in patients with gynecologic malignancy is rarely reported. We report an unusual presentation of venous gangrene of the lower limbs associated with warfarin therapy in a 53-year-old woman from the Cook Islands with an occult ovarian cancer.
METHODS: A 53-year-old woman of Cook Islands origin presented with exertional dyspnea, rapid atrial fibrillation, bilateral lower limb edema, and painful digital ischemia of her hallux. She was on warfarin therapy for atrial fibrillation and had a stable therapeutic international normalized ratio. Bilateral proximal lower limb deep vein thrombosis and digital gangrene subsequently developed in the setting of a supratherapeutic international normalized ratio and platelet count depletion. Her warfarin was reversed and heparin therapy was commenced with resulting correction of her thrombocytopenia.
CONCLUSIONS: We would like to attract the attention of the reader to the potential hazard of the use of warfarin in patients with malignancy. In our case, we also demonstrated a predictive value of supratherapeutic international normalized ratio and platelet count depletion that could herald massive thrombosis and gangrene in a patient who was previously stable on warfarin therapy. Early recognition and prompt reversal of warfarin in these circumstances is essential to correct the unbalanced prothrombotic process that leads to extensive thrombosis and gangrene. The outlook of such cases remains dismal and results in extensive morbidity and mortality.