Duration of Anticoagulation Therapy in Patients with Genetic Inherited Thrombophilia.

Background: Genetic factors play an important role in deep vein thrombosis (DVT). The duration of anticoagulation therapy in patients with verified genetic inheritance and previous events of DVT is still questionable. Case reports: We present three cases of siblings (two brothers and one sister) with verified Venous thromboembolism (VTE) and genetic inheritance. The first case is a 33 y.o. male who was admitted with bilateral massive pulmonary thromboembolism and DVT of the right femoral vein. He had an episode of DVT 4 years ago. Fibrinolytic therapy was introduced immediately. Afterwards, unfractionated heparin was introduced, and then switched to enoxaparin and acenocoumarol. Because of inappropriate INR, it was switched then to rivaroxaban. The imaging methods showed significant improvement, and the patient was discharged from the hospital with rivaroxaban at 2x15 mg/day for another 2 weeks and was instructed to continue 20 mg/day until his next control. In the meantime, the second case, a 36 y.o. male, brother to the first patient, came with vein thrombosis of vena saphena magna of the left leg. Treatment with Acenocoumarol was started and continued for 2 years until complete resolution of the thrombi, and then it was changed to Aspirin. The third case is the sister of the first 2 cases, a 38 y.o female with symptoms and findings almost similar to those in the second case. She was treated with Acenocoumarol for 6 months. Doppler ultrasound showed complete resolution of the thrombosis and anticoagulation therapy was stopped. Genetic investigations for mutation showed presence of homozygous gene mutation for Prothrombin (PTB G20210A) in the first patient, his brother (the second case) was compound heterozygote for PTB and for MTHFR C677T, and his sister (third case) was heterozygous only for the PTB mutation. According to the clinical (recurrent unprovoked DVT with thromboembolic complications) and genetic testing (homozygous gene mutation for PTB) in the first patient, we decided to continue the secondary thromboprophylaxis with rivaroxaban 10 mg/day indefinitely. Conclusion: Testing for genetically inherited thrombophilia should be included in the risk assessment for recurrence, and performed in all patients under 50 y.o. who have a first, non-provoked episode of thrombosis, in order to determine the duration of anticoagulation therapy.

Thrombophilia associated gene polymorphisms: Does use of medication, including anti-coagulants, minerals or folic acid, prevent the miscarriages?

OBJECTIVE: Recurrent pregnancy loss (RPL) has been associated with thrombophilia. The use of prophylactic treatments against thrombophilia becomes necessary in order to increase the live birth rates in women with RPL. The aim of this study was to genotype thrombophilia associated polymorphisms and investigates the benefit of prophylactic treatment on the clinical pregnancy outcomes of women with specific genotypes of these polymorphisms. MATERIALS AND METHODS: A total of 62 women were included in this study. The polymorphisms associated with thrombophilia, including methyltetrahydrofolate reductase (MTHFR) 1298 and 677, Factor V Leiden (FVL) 1691, plasminogen activator inhibitor-1 (PA1-1) G/G and Factor II prothrombin 20,210, were genotyped using the real time PCR. The effect of prophylactic treatment using anti-coagulants of 0.4 mL dose of enoxaparin (3000-6000IU) and 75 mg dose of aspirin, 81 mg dose of aspirin, mineral of 15 mg dose of zinco c or10 mg dose of folic acid, was correlated with the genotypes of polymorphisms. RESULTS AND CONCLUSION: The clinical pregnancy outcomes were significantly improved in patients with MTHFR 677CC genotype when treated with zinco c. Furthermore, treatment with 75 mg of aspirin resulted in higher negative pregnancy rates in patients with MTHFR A1298C genotypes. Therefore, the results of this study should be used to re-evaluate the clinical applications in women with miscarriages.

Risk of Cardiovascular Events and Mortality Among Elderly Patients With Reduced GFR Receiving Direct Oral Anticoagulants.

RATIONALE & OBJECTIVE: Evidence for the efficacy of direct oral anticoagulants (DOACs) to prevent cardiovascular (CV) events and mortality in older individuals with a low estimated glomerular filtration rate (eGFR) is lacking. We sought to characterize the association of oral anticoagulant use with CV morbidity in elderly patients with or without reductions in eGFRs, comparing DOACs with vitamin K antagonists (VKAs). STUDY DESIGN: Population-based retrospective cohort study. SETTINGS & PARTICIPANTS: All individuals 66 years or older with an initial prescription for oral anticoagulants dispensed in Ontario, Canada, from 2009 to 2016. EXPOSURE: DOACs (apixaban, dabigatran, and rivaroxaban) compared with VKAs by eGFR group (≥60, 30-59, and<30mL/min/1.73m2). OUTCOMES: The primary outcome was a composite of a CV event (myocardial infarction, revascularization, or ischemic stroke) or mortality. Secondary outcomes were CV events alone, mortality, and hemorrhage requiring hospitalization. ANALYTICAL APPROACH: High-dimensional propensity score matching of DOAC to VKA users and Cox proportional hazards regression. RESULTS: 27,552 new DOAC users were matched to 27,552 new VKA users (median age, 78 years; 49% women). There was significantly lower risk for CV events or mortality among DOAC users compared with VKA users (event rates of 79.78 vs 99.77 per 1,000 person-years, respectively; HR, 0.82 [95% CI, 0.75-0.90]) and lower risk for hemorrhage (event rates of 10.35 vs 16.77 per 1,000 person-years, respectively; HR, 0.73 [95% CI, 0.58-0.91]). There was an interaction between eGFR and the association of anticoagulant class with the primary composite outcome (P<0.02): HRs of 1.01 [95% CI, 0.92-1.12], 0.83 [95% CI, 0.75-0.93], and 0.75 [95% CI, 0.51-1.10] for eGFRs of≥60, 30 to 59, and<30mL/min/1.73m2. No interaction was detected for the outcome of hemorrhage. LIMITATIONS: Retrospective observational study design limits causal inference; dosages of DOACs and international normalized ratio values were not available; low event rates in some subgroups limited statistical power. CONCLUSIONS: DOACs compared with VKAs were associated with lower risk for the composite of CV events or mortality, an association for which the strength was most apparent among those with reduced eGFRs. The therapeutic implications of these findings await further study.

ß-Thalassemia intermedia: a comprehensive overview and novel approaches.

ß-Thalassemia intermedia is a clinical condition of intermediate gravity between ß-thalassemia minor, the asymptomatic carrier, and ß-thalassemia major, the transfusion-dependent severe anemia. It is characterized by a significant clinical polymorphism, which is attributable to its genetic heterogeneity. Ineffective erythropoiesis, chronic anemia, and iron overload contribute to the clinical complications of thalassemia intermedia through stepwise pathophysiological mechanisms. These complications, including splenomegaly, extramedullary erythropoiesis, iron accumulation, leg ulcers, thrombophilia, and bone abnormalities can be managed via fetal hemoglobin induction, occasional transfusions, chelation, and in some cases, stem cell transplantation. Given its clinical diversity, thalassemia intermedia patients require tailored approaches to therapy. Here we present an overview and novel approaches to the genetic basis, pathophysiological mechanisms, clinical complications, and optimal management of thalassemia intermedia.

Bilateral thalamic stroke in patient with patent foramen ovale and hereditary thrombophilia.

Patent foramen ovale and hereditary thrombophilia are both known risk factors for ischemic stroke. Artery of Percheron is a rare anatomical variant in which vast areas of the midbrain and thalamus have a single source of blood supply. This case report presents a 45-years old female patient with bilateral thalamic stroke due to Percheron artery occlusion, with a combination of hereditary thrombophilia and patent foramen ovale as the risk factors. Modern approaches to the diagnosis and secondary prevention of this pathology are also discussed herein.

[RESULTS OF PREPARATION AND IMPLEMENTATION OF IVF PROGRAM IN PATIENTS WITH THROMBOPHILIA AND HISTORY OF FAILED IVF].

The problem of infertility and reproductive losses maintains its urgency, as well as medical and social significance. Frequency of infertility in overall population, according to the data from different authors, varies from 9 to 18 per cent. Methods of aided reproductive technologies (ART) opened a new era in the field of correction of infertile marriage. As a result, more and more couples choose to solve this problem by means of aided reproductive technologies (ART): in-vitro fertilization (IVF) and embryo transfer (ET). However, despite of all achievements, the frequency of pregnancy development remains relatively low and makes 25-30% per treatment cycle, furthermore, during the last decade this value did not change to any significant extent. Analysis of literature sources revealed that genetic, acquired and combined forms of thrombophilia, which often cause severe complications at ART, are among main causes of IVF failures. The aim of the research was to develop and to introduce main principles of prophylaxis of repeated IVF failures in women with thrombophilia and history of failed IVF. In order to achieve the goal we have examined 80 patients (main group) with genetic, acquired or combined thrombophilia, identified on the first stage of standard examination. One of the main reasons of IVF failure is genetic, acquired or combined thrombophilia. Delivery of pathogenetically justified antithrombotic prophylaxis (75 mg. of aspirin and low molecular heparin - enoxaparinum) in patients with thrombophilia and history of failed IVFs allowed improvement of hemostasiogram profile and efficiency of IVF. Frequency of pregnancy in patients with history of failed IVF after the therapy made 31,3% in the first cycle of simulation (in 25 women), 20,0% in the second cycle of simulation (in 16 women) and 11,3% (9 women) in the third cycle. Due to justified antithrombotic prophylaxis 50 cases of pregnancy was registered (62,5%). Introduction of long-term therapy with application of antithrombotic preparations and vitamins in continuous mode promoted successful course of pregnancy, occurred as a result of IVF in patients with history of failed IVF.

Non-vitamin K antagonist oral anticoagulants in patients with severe inherited thrombophilia: a series of 33 patients.

: The aim of the study was to investigate whether treatment with non-vitamin K antagonist oral anticoagulants (NOACs) is effective and well tolerated in real-life patients following venous thromboembolism (VTE) associated with severe inherited thrombophilia. We evaluated 33 consecutive patients with severe inherited thrombophilia, defined as the presence of deficiencies in protein C, protein S, or anti-thrombin, homozygous factor V Leiden and prothrombin G20210A mutations, or combined defects. The patients were recruited from March 2010 to December 2015 and followed till July 2016. Rivaroxaban was used in 23 patients (70%), whereas dabigatran and apixaban were used in 4 patients each. During a median 21 (range 8-34) months' follow-up, three recurrent VTE episodes (9%) were observed. Deep vein thrombosis recurred after 6 months on rivaroxaban in a protein S-deficient 32-year-old woman who had heavy menstrual bleeding resulting in interruptions of therapy. A long journey preceded deep vein thrombosis recurrence after 12 months of rivaroxaban use in a 59-year-old obese man homozygous for prothrombin 20210A mutation. The third recurrent VTE following anticoagulation withdrawal prior to surgery and during hospitalization was observed in a 56-year-old woman with protein S deficiency and heterozygous factor V Leiden. The three patients continued use of NOACs, apixaban, dabigatran, and rivaroxaban, respectively. This largest real-life series of patients with severe thrombophilia receiving NOACs indicates that such patients could be safely and effectively treated with NOACs. Lower efficacy was observed in protein S deficiency. Recurrent VTE was mostly related with nonadherence, which highlights an important role of regular intake of NOACs in high-risk patients.

Diagnosis and management of idiopathic facial palsy in children.

Idiopathic or Bell's palsy is an acute peripheral-nerve palsy involving the facial nerve. The disorder is quite infrequent under the age of 10 years. The proposed etiologies of Bell's palsy include ischemic neuropathy and vascular diseases. This case series presents five children with Bell's palsy. The epidemiologic, diagnostic and therapeutic measures were summarized. The evolution regarding especially the facial motricity was detailed. The results about the role of some thrombophilic polymorphisms suggest a probable involvement of factor V haplotype, MTHFR and factor XIII in the etiology of Bell's palsy in five Tunisian children.

[Managing antithrombotic therapy in vitreoretinal surgery]. / Comment gérer les antithrombotiques en chirurgie vitréorétinienne ?

Given the growing number of patients on antithrombotic therapy we are increasingly confronted with the management of this therapy before, during and after vitreoretinal surgery. In the absence of a consensus, the decision to withdraw antithrombotic therapy is based on the cardiovascular thromboembolism risk versus the theoretical risk of bleeding if the antithrombotic treatment is continued. As suggested by the literature, antiplatelet therapy (acetylsalicylic acid or clopidogrel) may be safely continued for vitreoretinal surgery, including retinal detachment repair. However, the risk/benefit ratio for patients being treated with two antiplatelet therapies is unknown. It appears that an International Normalized Ratio (INR) less than 3 for patients treated with anticoagulant therapy does not increase the perioperative risk of ocular bleeding. This risk has not been evaluated in patients treated by new antithrombotic therapies (prasugrel, ticagrelor as antiplatelet medication, or dabigatran, rivaroxaban, apixaban as anticoagulant therapy), and there is a need to study it further.

Use of rivaroxaban in a patient with history of nephrotic syndrome and hypercoagulability.

OBJECTIVE: Hypercoagulability, resulting in thromboembolic events, can be a life-threatening complication of nephrotic syndrome (NS). Conventional anticoagulants, such as warfarin, have been the standard of care for more than 50 years; however, the availability of target-specific oral anticoagulants (TSOACs) have provided additional options for the treatment and prevention of thromboembolic events. Documented use of the TSOACs in patients with NS and hypercoagulability is currently limited. CASE SUMMARY: We present the case of an 18-year-old young woman with NS and renal vein thrombosis who was readmitted with bilateral pulmonary emboli on therapeutic doses of warfarin, with a goal international normalized ratio of 2.0 to 3.0. The decision was made to transition the patient from warfarin to rivaroxaban, an oral factor Xa inhibitor. DISCUSSION: Rivaroxaban was the first of the emerging TSOACs to be FDA approved for both prevention and treatment of venous thromboembolism. With favorable safety and efficacy data compared with warfarin in addition to a predictable pharmacokinetic profile and the lack of requirement of routine monitoring, rivaroxaban provides a useful alternative in this patient population. SUMMARY: While on therapeutic anticoagulation, a patient previously diagnosed with NS and renal vein thrombosis experienced pulmonary emboli on a conventional anticoagulant and was switched to a target-specific oral anticoagulant with documented completion of 6 months of therapy without recurrent thromboembolism.

Inherited Thrombophilia.

Thrombophilia alters normal hemostasis, shifting the balance in favor of thrombus formation. Inherited conditions include factor V Leiden (FVL), prothrombin G20210A mutation, deficiencies in natural anticoagulants (antithrombin [AT], protein C, and protein S), hyperhomocysteinemia, and elevations in clotting factors (factors VIII and XI). Although FVL and prothrombin mutation are common disorders, deficiencies in the natural anticoagulants are rare. The risk of initial thrombosis conferred by inherited thrombophilia varies with the highest risk in those homozygous for either FVL or prothrombin mutation, or with AT deficiency. In the nonpregnant patient, the presence of a thrombophilia does not affect treatment of an acute event. Although vitamin B supplementation has been shown to decrease the levels of homocysteine, the treatment has failed to show a benefit in thrombus prevention and is therefore not recommended.

The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: new scenarios and opportunities.

The risk of recurrent thromboembolic disorders in the 10-year period following an episode of unprovoked venous thromboembolism (VTE) ranges between 30 and 50%, the rate being higher in patients with primary deep venous thrombosis (DVT) than in those with primary pulmonary embolism (PE). The clinical presentation with primary PE increases by more than three times the risk of a new PE episode over that with isolated DVT. Baseline parameters that increase this risk are the proximal location of DVT, obesity, old age and male sex, whereas the role of thrombophilia is controversial. An increasing role is played by post-baseline parameters such as the ultrasound assessment of residual vein thrombosis and the determination of D-dimer. While the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, new scenarios are being offered by the identification of risk stratification models and by strategies that have the potential to help identify patients in whom anticoagulation can be safely discontinued, such as those that incorporate the assessment of D-dimer and residual vein thrombosis. New opportunities are being offered by low-dose aspirin, which has recently been reported to decrease by more than 30% the risk of recurrent events without increasing the bleeding risk; and especially by a few emerging anti-Xa and anti-IIa oral compounds, which are likely to induce fewer haemorrhagic complications than vitamin K antagonists while preserving at least the same effectiveness, do not require laboratory monitoring, and can be used immediately after the thrombotic episode.

Rivaroxaban is as efficient and safe as bemiparin as thromboprophylaxis in knee arthroscopy.

PURPOSE: The aim of this study is to compare effectiveness and safety profile of rivaroxaban with bemiparin in 3-week extended prophylaxis after knee arthroscopy. METHODS: Four hundred and sixty-seven patients were included in this review divided in two groups. One followed prophylaxis with rivaroxaban and the other one with bemiparin. All patients were interviewed and explored at 1 and 3 months postoperatively, looking for symptomatic signs of deep-vein thrombosis (DVT). In case of suspicion, diagnostic tests were performed. Collected data were age, sex, gender, diagnosis, time with ischemia, body mass index, concomitant diseases, concomitant therapy, DVT signs, treatment satisfaction, minor and major complications, treatment adherence and tolerability. RESULTS: No thromboembolic events were observed in any of the groups. In one case treated with rivaroxaban, the drug had to be withdrawn due to epistaxis. CONCLUSIONS: Our study showed that extended prophylaxis with 10 mg of rivaroxaban once daily for 3 weeks resulted as effective as bemiparin in knee arthroscopy thromboprophylaxis.

Bilateral consecutive optic neuropathy in a patient with thrombophilia.

A 39-year-old man was admitted with a sudden visual loss in the left eye. Visual acuities were 10/10 on the right and 1/10 on the left. Fundus examination did not show any abnormalities. Visual acuity improved to 10/10 and visual field defect regressed in the following 2 weeks. Three years later, the patient returned with acute visual loss in the right eye. Visual acuities were 2/10 on the right and 10/10 on the left. Right optic disc had blurred margins with mild oedema. The tests revealed methylenetetrahydrofolate reductase A1298C mutation with positive lupus anticoagulant and hyperhomocysteinaemia. Enoxaparin was initialised with vitamin B12 supplementation. Complete visual recovery occurred in the following 3 weeks in both eyes. Thrombophilic screening seems to be important in the treatment and prevention of an attack in the second eye of patients with non-arteritic anterior ischaemic optic neuropathy.

To be or not to be: the patient's view of thrombophilia testing.

INTRODUCTION: The literature on the psychological effects of thrombophilia testing is unclear. Little is known about the complex world of significance subjects construct around the test. OBJECTIVE: The study explored the peculiar network of implicit meanings that may be linked to the experience of being tested. MATERIALS AND METHODS: The research was designed according to Interpretative Phenomenological Analysis (IPA). 19 patients were interviewed. Integral verbatim reports of the interviews were analyzed through an inductive process aimed at gaining a holistic understanding of the narratives. RESULTS: Two main issues were identified, each with sub-issues: (1) the clinical problem: (1.1) unhealthy blood and (1.2) the family issue; (2) the test: (2.1) knowing for the sake of knowing; (2.2) knowing for the sake of doing; (2.3) not knowing. CONCLUSIONS: The thrombophilia test is part of a larger network of meanings, where information about the test and its results seem to be lost. PRACTICE IMPLICATION: The study suggests the importance of paying greater attention to the process of doctor-patient communication at the time of the test. The theme of being informed is important for patients, yet often they are not able to understand or retain the information they receive, increasing the risk of misunderstandings.

Anticoagulating obese patients in the modern era.

The prevalence of obesity has increased substantially over recent years. Clinicians are increasingly being challenged with making uncertain anticoagulant dosing decisions, as the optimal dosing strategy for most anticoagulants in the obese patient population remains unknown. Research published to date suggests that the clearance of anticoagulants increases with weight. As obesity is associated with an increased risk of venous thromboembolism and arterial disease, there is an urgent need to establish appropriate anticoagulation regimens for this patient group. Research studies applying the method of pharmacokinetic-pharmacodynamic modelling and simulation could establish an appropriate evidence base and provide direction and reassurance to prescribing clinicians.

Blood management in pediatric spinal deformity surgery: review of a 2-year experience.

BACKGROUND: Pediatric scoliosis surgery is associated with considerable blood loss and allogenic transfusions. Transfusions contribute to morbidities and cost. A perioperative pediatric blood management program was implemented at our institution. Patients received preoperative evaluation, cell salvage, topical hemostasis, antifibrinolytics, and hypotensive anesthesia. STUDY DESIGN AND METHODS: The study was a 2-year retrospective cohort review of the program's population from September 2007 through August 2009. RESULTS: A total of 110 scoliosis surgeries were performed with only 34 and 12% of the patients requiring preoperative oral iron and erythropoietin, respectively. Neuromuscular scoliosis patients had more repaired segments and a larger transfusion rate than idiopathic scoliosis patients (36% vs. 1.7%, p = 0.001). Transfused patients had more blood loss relative to their blood volume (p = 0.001) and blood loss was associated with higher Cobb angles (p = 0.04). Logistic regression revealed that blood loss (p = 0.001), number of segments fused (p = 0.004), and lower patient weight (p = 0.007) are associated with increased odds for transfusion. Twelve patients (10.9%) were identified with low von Willebrand activity with a trend toward higher blood losses (p = 0.07) with lower activity levels. CONCLUSION: Transfusion requirements in scoliosis patients are dependent on blood loss as determined by Cobb angles and number of segments fused relative to the patients' blood volume as determined by weight. Implementation of a blood management protocol resulted in a low transfusion rate and unexpectedly led to the preoperative diagnosis of a number of patients with low levels of von Willebrand activity.

Anterior spinal artery syndrome in a 13-year-old boy 8 days after taekwondo-fight: vascular obliteration due to vessel lesion or thrombophilia?

BACKGROUND: Spinal cord infarction from anterior spinal cord syndrome (ASAS) in children is a rare pathology and comprises the following clinical symptoms: sudden onset of pain and flaccid para- or tetraparesis, bladder dysfunction, and dissociated sensory loss with impairment of pain and temperature perception. Deep sensibility is not affected. PATIENT: A 13-year-old male patient presented to our emergency department with a bilateral leg weakness. 1 week before, he had suffered a leg strain in a Taekwondo-fight from which he recovered completely. On physical examination our patient's legs were in flaccid paralysis, tone was decreased and he had dissociated sensory loss and acute retention of urine. Blood count, ESR, electrolytes, serologic tests for various pathogens and CSF examination all were normal. However, tests for values of an acute endothelial lesion were increased and he was a homozygous carrier of MTHFR-polymorphism. MRI performed on the day of admission was normal but showed dramatic changes 2 days later with increased signal intensity in the ventral aspect of the spinal cord, characteristic for an ASAS. Treatment included highdose methylprednisolone, a suprapubic bladder catheter, sufficient anticoagulation and a rapid transfer to a rehabilitation centre. DISCUSSION: We assume that a combination of the patient's prothrombotic risk factor (MTHFR-polymorphism with elevated homocysteine levels) and his trauma in the taekwondo-fight with consecutive vessel injury caused an occlusion of the artery by late emboli or a growing thrombus.

Atherothrombosis in 2 vascular territories in a young woman: importance of thrombophilia testing.

The diagnosis and management of complex and multiple inherited thrombophilias is still a challenge for the clinicians involved in this field, clinical events being the result of the interaction between genes, environmental or other acquired factors, and age. Moreover, various clinical manifestations as regards severity or type of event (venous or arterial thrombotic event, obstetrical complications) are cited in these patients. We present the case of a 20-year-old woman, with a 2-month history of third-generation contraceptive use and with recently diagnosed hypercholesterolemia, who presented ischemic events in 2 arterial territories: acute left lower limb ischemia and silent myocardial infarction. Screening tests for thrombophilia, including genetic testing, showed moderate hyperhomocysteinemia and 2 inherited thrombophilic defects. Invasive investigation of the coronary arteries showed the presence of advanced atherosclerotic disease. Management of this complex thrombophilia includes lifetime oral anticoagulation as well as a homocysteine-lowering strategy comprising lifestyle modification and group B (folic acid, B(6), B(12)) vitamin supplementing.

Protection in rats with heatstroke: hyperbaric oxygen vs activated protein C therapy.

The present study was attempted to evaluate the therapeutic effects of activated protein C and/or hyperbaric oxygen in an animal model of heatstroke. Sixty-eight minutes heat stress (43 degrees C) initiated, the anesthetized rats were randomized to several groups and administered: 1) no resuscitation (vehicle solution plus normabaric air, 2) intravenous activated protein C (1mg in 1ml of normal saline per kg of body weight), 3) hyperbaric oxygen (100% oxygen at 202kpa for 17min), and 4) intravenous activated protein C plus hyperbaric oxygen. Another group of rats exposed to room temperature (26 degrees C) was used as normothermic controls. Blood sampling was 0min, 70min, and 85min after heat stress initiated. When the vehicle-treated rats underwent heat exposure, their survival time values found were to be 19-25min. Resuscitation with activated protein C or hyperbaric oxygen significantly and equally improved survival during heatstroke (134-159min). As compared with those of activated protein C or hyperbaric oxygen alone, combined activated protein C and hyperbaric oxygen significantly had higher survival time values (277-347min). All vehicle-treated heatstroke animals displayed systemic response, hypercoagulable state, and hepatic and renal dysfunction. Combined activated protein C and hyperbaric oxygen therapy reduced these heatstroke reactions better than activated protein C or hyperbaric oxygen alone. The results indicate consequently, combined activated protein C and hyperbaric oxygen therapy heightens benefit in combating heatstroke reactions.