The effect of DOACs on laboratory tests and their removal by activated carbon to limit interference in functional assays.

We aimed to review the interfering effect of DOACs on tests for haemostatic function and then to discuss overcoming these with activated carbon (AC) products, thereby eliminating DOAC issues from test plasmas. Recent relevant articles were reviewed and are discussed. Laboratory tests for DOACs, lupus anticoagulant, factor assays and APC Resistance were carried out in such publications with and without an AC product on various instruments using reagents approved for diagnostic use in well-regulated clinical laboratories. All reports on this plasma pre-treatment by AC products agree that they extract DOACs from plasma samples with minimal effect on underlying clotting tests. The specific extraction of DOACs significantly reduced false positive lupus anticoagulant detection and provided more reliable results in clotting factor assays, APC resistance and other thrombophilia tests. Dabigatran and edoxaban seem to be adsorbed more thoroughly by AC from plasmas than rivaroxaban and apixaban. In summary, most of the AC products reviewed here appear to remove DOACs from test plasmas without significantly affecting underlying clotting tests and permit correct diagnosis of various haemostatic conditions despite the initial presence of DOACs. The application of such agents as a sample pre-treatment to overcome the effects of DOACs for routine coagulation testing is supported by the emerging literature.

Rivaroxaban Causes Missed Diagnosis of Protein S Deficiency but Not of Activated Protein C Resistance (Factor V Leiden).

CONTEXT: - Rivaroxaban causes a false increase in activated protein C resistance (APCR) ratios and protein S activity. OBJECTIVE: - To investigate whether this increase masks a diagnosis of factor V Leiden (FVL) or protein S deficiency in a "real-world" population of patients undergoing rivaroxaban treatment and hypercoagulation testing. DESIGN: - During a 2.5-year period, we compared 4 groups of patients (n = 60): FVL heterozygous (FVL-HET)/taking rivaroxaban, wild-type/taking rivaroxaban, FVL-HET/no rivaroxaban, and normal APCR/no rivaroxaban. Patients taking rivaroxaban were tested for protein S functional activity and free antigen (n = 32). RESULTS: - The FVL-HET patients taking rivaroxaban had lower APCR ratios than wild-type patients ( P < .001). For FVL-HET patients taking rivaroxaban, mean APCR was 1.75 ± 0.12, versus 1.64 ± 0.3 in FVL-HET patients not taking rivaroxaban ( P = .005). Activated protein C resistance in FVL-HET patients fell more than 3 SDs below the cutoff of 2.2 at which the laboratory reflexes FVL DNA testing. No cases of FVL were missed despite rivaroxaban. In contrast, rivaroxaban falsely elevated functional protein S activity, regardless of the presence or absence of FVL ( P < .001). A total of 4 of 32 patients (12.5%) had low free protein S antigen (range, 58%-67%), whereas their functional protein S activity appeared normal (range 75%-130%). Rivaroxaban would have caused a missed diagnosis of all cases of protein S deficiency during the study if testing relied on the protein S activity assay alone. CONCLUSIONS: - Despite rivaroxaban treatment, APCR testing can distinguish FVL-HET from normal patients, rendering indiscriminate FVL DNA testing of all patients on rivaroxaban unnecessary. Free protein S should be tested in patients taking rivaroxaban to exclude hereditary protein S deficiency.

[Pulmonary Embolism Despite Rivaroxaban in an Obese Patient]. / Pulmonalembolie trotz Rivaroxaban bei einer adipösen Patientin.

Introduction Rivaroxaban, an oral factor Xa inhibitor, is approved for therapy of venous thromboembolism. It is unclear whether the standard dose for patients with a body mass index (BMI) > 40 kg/m2 is sufficient. History The 45-year-old patient was admitted because of increasing respiratory distress. She had a history of pulmonary embolism 30 months before the admission, a factor V Leiden mutation and several hospitalisations due to dermatomycoses. The patient briefly took phenprocoumon which was changed to 20 mg rivaroxaban due to a lack of adherence. Six months before admission, the patient paused the rivaroxaban therapy because of dental surgery and suffered a recurrent pulmonary embolism. Findings and Diagnosis The patient presented with increasing difficulty of breathing, morbid obesity with a BMI of 59.3 kg/m2 and intertrigo of the lower extremities. The ECG showed a right axis deviation, a pulmonary P-wave and an incomplete right bundle branch block. Computed tomography showed pulmonary embolisms of the left lower lobe. The pulmonary artery was dilated, and the right atrium was enlarged. Venous thrombosis of the lower limb could not be certainly ruled out. The D-dimer was elevated with 5.895 mg/L (normal value up to 169 mg/L) and NT-pro-BNP was elevated at 5.580 ng/L (normal value up to 0.5 ng/L). Sixteen hours after the onset of symptoms, 22 hours after the last dose, the serum rivaroxaban level was 137 ng/ml. According to manufacturers, the therapeutic range of rivaroxaban after 2 - 4 hours is 22 - 535 ng/ml, and after 24 hours 6 - 239 ng/ml. Therapy and course After initiation of a therapy with low-molecular weight heparin and subsequent oral anticoagulation with phenprocoumon, the symptoms decreased. Conclusions It is highly probable that the pulmonary embolism occurred at a time when the rivaroxaban level was in the therapeutic range. Since there are only few data about safety and efficacy of rivaroxaban and other non-vitamin K-oral anticoagulants (NOACs) in severely obese patients, the recommendations of the "International Society for Thrombosis and Haemostasis" should be followed: Rivaroxaban and other NOACs should not be used in patients with a BMI > 40 kg/m2 or weight > 120 kg, since only few data on this patient group are available. If NOACs are necessary in these patients, serum concentrations of NOACs should be measured.

Successful Living-Related Renal Allograft in a Recipient With Factor V Leiden Deficiency: A Case Report.

Thrombophilia due to activated protein C resistance (Leiden mutation) is the most common inherited thrombophilic disorder with 5% incidence in whites. Renal transplant of these patients entails a risk of vascular thrombosis soon after the transplant; and acute rejection episodes and graft loss within the first year. We present a case of a successful living-related renal transplant in man with a recent history of repeat episodes of vascular access thrombosis attributed to inherited thrombophilia (heterozygosity for factor V mutation Q506 and homozygosity for mutation T677 for methylene-tetrahydrofolate reductase). Transplant recipient was administered anticoagulation therapy with low molecular weight heparin pre- and postoperatively. No thrombotic or hemorrhagic events occurred posttransplant. A high suspicion of thrombophilic disorders in patients with end-stage renal disease with vascular access thrombotic events should be screened further to prevent failure of a subsequent renal transplant. Inherited thrombophilic disorders may not exclude living-related kidney transplant provided that anticoagulation therapy is admin-istered perioperatively.

Low molecular weight heparin modulates maternal immune response in pregnant women and mice with thrombophilia.

PROBLEM: Thrombophilia is associated with pregnancy complications. Treatment with low molecular weight heparin (LMWH) improves pregnancy outcome, but the underlying mechanisms are not clear. METHODS OF STUDY: We analyzed Treg frequency in blood from thrombophilic pregnancies treated with LMWH (n = 32) or untreated (n = 33) and from healthy pregnancies (n = 39) at all trimesters. Additionally, we treated pregnant wild-type, heterozygous and homozygous factor-V-Leiden (FVL) mice with LMWH or PBS and determined Treg frequency, pro-/anti-inflammatory cytokine levels and Caspase-3-activity in placenta and decidua. RESULTS: Treg frequencies were increased in second and third trimester in LMWH-treated thrombophilic pregnancies compared to controls. Treg levels were comparable to those of normal pregnancies. Homozygous FVL mice had decreased decidual Tregs compared to wild-type mice. LMWH treatment normalized Tregs and was associated with increased decidual IL-10 mRNA. LMWH diminished Caspase-3-activity in mice of all genotypes. CONCLUSION: We demonstrated anti-apoptotic and anti-inflammatory effects of LMWH in pregnant FVL mice. LMWH increased Treg levels in mice and humans, which suggests benefits of LMWH treatment for thrombophilic women during pregnancy.

Pregnancy in a patient with hepatic artery thrombosis after liver transplantation: a case report.

BACKGROUND: Hepatic artery thrombosis (HAT) increases the risk of complications and mortality after liver transplantation. The incidence for HAT is increased in patients with risk factors (vascular reconstructions, coagulation disorders and acute rejection episodes amongst others). Early retransplantation improves the prognosis for patients, but owing to lack of donors, surgical and interventional radiologic attempts to restore the patency of hepatic artery are made. The prognosis for the liver and the patient can also be improved by the development of collateral circulation. CASE REPORT: We describe a case of a 30-year-old woman with hepatic failure owing to Wilson disease. Liver transplantation with the use of vascular conduit made of donor's iliac arteries was complicated by an early HAT. Heterozygous factor V Leiden mutation was confirmed in the patient. Despite surgical and radiologic attempts to restore patency and despite treatment with fractioned heparin and aspirin, the hepatic artery remained occluded. Retransplantation was not considered, even though the patient was planning a pregnancy. After 1 year of observation of stable liver function, conversion from mycophenolate mofetil to azathioprine treatment, the patient was given consent for a high-risk pregnancy. DISCUSSION: The course of pregnancy was uneventful, with normal liver function parameters, without pathological bleedings. The patient was treated with doses of enoxaparin adjusted for the patient's weight. In the 34th week, owing to increasing concentration of bile acids, the pregnancy ended with a cesarean section. The newborn had 10-point APGAR score.

Congenital anomaly of the inferior vena cava and factor V Leiden mutation predisposing to deep vein thrombosis.

A previously healthy 21-year-old man presented with back pain, bilateral extremity pain, and right lower extremity weakness, paresthesias, and swelling. Sonographic examination revealed diffuse deep vein thrombosis (DVT) in the femoral and popliteal venous system. CT imaging revealed hypoplasia of the hepatic inferior vena cava (IVC) segment with formation of multiple varices and collateral veins around the kidneys. Hematologic workup also discovered a factor V Leiden mutation, further predisposing the patient to DVT. The rare, often overlooked occurrence of attenuated IVC, especially in the setting of hypercoagulable state, can predispose patients to significant thrombosis.

Anti-protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome.

BACKGROUND: Antiphospholipid antibodies may interfere with the anticoagulant activity of activated protein C (APC) to induce acquired APC resistance (APCr). AIMS: To investigate the frequency and characteristics of APCr by using recombinant human APC (rhAPC) and endogenous protein C activation in antiphospholipid syndrome (APS). METHODS: APCr was assessed in APS and non-APS venous thromboembolism (VTE) patients on warfarin and normal controls with rhAPC or Protac by thrombin generation. IgG anti-protein C and anti-protein S antibodies and avidity were assessed by ELISA. RESULTS: APS patients showed greater resistance to both rhAPC and Protac than non-APS patients and normal controls (median normalized endogenous thrombin potential inhibition): APS patients with rhAPC, 81.3% (95% confidence interval [CI] 75.2-88.3%; non-APS patients with rhAPC, 97.7% (95% CI 93.6-101.8%; APS patients with Protac, 66.0% (95% CI 59.5-72.6%); and non-APS patients with Protac, 80.7 (95% CI 74.2-87.2%). APS patients also had a higher frequency and higher levels of anti-protein C antibodies, with 60% (15/25) high-avidity antibodies. High-avidity anti-protein C antibodies were associated with greater APCr and with a severe thrombotic phenotype (defined as the development of recurrent VTE while patients were receiving therapeutic anticoagulation or both venous and arterial thrombosis). Twelve of 15 (80%) patients with high-avidity anti-protein C antibodies were classified as APS category I. CONCLUSION: Thrombotic APS patients showed greater APCr to both rhAPC and activation of endogenous protein C by Protac. High-avidity anti-protein C antibodies, associated with greater APCr, may provide a marker for a severe thrombotic phenotype in APS. However, in patients with category I APS, it remains to be established whether anti-protein C or anti-ß2 -glycoprotein I antibodies are responsible for APCr.

Mesenteric vein thrombosis in a patient heterozygous for factor V Leiden and G20210A prothrombin genotypes.

Mesenteric venous thrombosis (MVT) is a rare but life threatening form of bowel ischemia. It is implicated in 6%-9% of all cases of acute mesenteric ischemia. The proportion of patients with primary (or idiopathic) MVT varies from 0% to 49%, with a decrease in frequency secondary to more recent availability of newer investigations for hypercoagulability. The presence of factor V Leiden (FVL) and prothrombin G20210A mutations (PGM) have been well documented in these cases. However, there have been scarce case reports describing MVT in heterozygotes of both these mutations occurring simultaneously and its implications on long term management. Our case describes acute MVT in a previously asymptomatic young patient with no prior history of venous thromboembolism. The patient was found to be heterozygous for FVL and PGM and treated with lifelong anticoagulation with warfarin (goal international normalized ratio: 2-3) and avoidance of hormonal contraceptives.

A 30-year-old industrial worker with upper back pain.

This column presents the case of a 30-year-old man seeking care for upper back pain at a freestanding emergency center. His occupation involved carrying 50-lb buckets of chemicals up ladders to the rooftops of industrial buildings. Back pain is a common complaint in emergency departments and most often musculoskeletal in nature. In this case, the back pain was not musculoskeletal but resulted from bilateral pulmonary emboli. The patient did not know that he had Factor V Leiden disorder. This column emphasizes the importance of ruling out serious life-threatening conditions in patients who present with common complaints and no traditional red flag symptoms.

[Resistance to warfarin in a patient with hereditary thrombophilia]. / Warfarinresistens hos en patient med hereditær trombofili.

We present a case report of a young man with spontaneous deep venous thrombosis. He tested positive for heterozygote factor V Leiden mutation and was treated with warfarin. However, he turned out to be resistant to warfarin, and another venous thrombosis occurred during the insufficient treatment. The antithrombotic treatment was then successfully replaced by phenprocoumon. This case report emphasizes the importance of critically evaluating the efficacy of a treatment and substitute if proven insufficient.

Acquired activated protein C resistance in sarcoma patients.

Acquired activated protein C resistance (aAPCR) is seen more frequently in solid and hematological cancer patients. We aimed to investigate the presence of aAPCR and the frequency of clinically detectable thrombosis in sarcoma patients. Normalized activated protein C sensitivity ratio (nAPCSR), factor V Leiden (FVL) mutation, factor V (FV) levels and factor VIII (FVIII) levels were prospectively measured in 52 patients and in 52 healthy controls. Clinically detectable thrombosis was present in one patient (1.92%). Compared with healthy controls (106%), the sarcoma patients had significantly lower values of the nAPCSR at pre (87.25%) and post (94.35%) treatment period (P < 0.0001). aAPCR was found as 4.2, 13 and 0%, respectively. The post-treatment FV levels (178.1 U/dl) were significantly (P < 0.001) higher than the pretreatment levels (147.5 U/dl). Inverse correlation was found between post-treatment FV levels and nAPCSR values (r = -0.38, P < 0.02). We found out a slightly increased frequency of venous thromboembolism in sarcoma patients. As an original finding which has not been reported previously in the literature, we also found out a decrease in the nAPCSR, persisting even after treatment. Thirdly, we found out that the significantly higher rate of aAPCR at the time of diagnosis totally disappeared after treatment.

Lupus anticoagulant interference in activated protein C resistance testing: in vitro phenomenon or in vivo pathophysiologic effect?

Second-generation activated protein C resistance (APC-R) assay was developed to avert interferences from lupus anticoagulant (LA) and warfarin therapy by prediluting the patient sample with factor V (FV)-depleted plasma. We investigated the effect of LA on the second generation APC-R assay in 121 LA-positive patients. Twenty-five APC-R-positive patients were tested for the mutation in FV (Leiden, Hong Kong, and Cambridge). Eleven had FV Leiden and twelve were negative for any mutation (2 were not tested). Of 12, 8 had APC-R suggestive of heterozygous and 4 had APC-R suggestive of homozygous defects. These patients had strong LA activity, compared to those with concurrent FVL. This was associated with a trend toward increased thrombosis risk compared to those with normal APC-R. These findings suggest that LA causes acquired APC-R, reflecting an in vivo pathophysiologic effect of LA rather than merely an in vitro phenomenon even with the second generation APC-R assay.

Activated protein C resistance, factor V Leiden and assessment of thrombotic risk.

Venous thromboembolism comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). Acute venous thromboembolism (VTE) is a serious and potentially fatal disorder which often complicates the course of hospitalized patients, but also affects ambulatory and otherwise healthy people. The annual incidence of venous thromboembolism is 1 to 2 cases per 1000 person and the risk of the disorder rises exponentially with age, from an annual rate of less than 5 per 100,000 children to greater than 400 per 100,000 adults older than 80 years.

Hirudin treatment for multiple thromboses in a preterm infant with inherited thrombophilia.

Thromboembolic events in preterm infants constitute a serious problem in neonatal intensive care. In most cases, treatment with low-molecular-weight heparin offers a sufficient therapy of thrombotic events. We report the case of a severely sick male preterm infant with a heterozygous factor V Leiden mutation and protein C deficiency. The infant developed multiple thromboses despite adequate anticoagulation with enoxaparin and was in a life-threatening situation. Treatment with hirudin prevented the occurrence of new thromboses without causing bleeding complications. After 2 weeks hirudin was discontinued and low-molecular-weight heparin therapy was started again. A successive recanalization of the vast majority of affected vessels was observed within the following 6 months. Despite some minor neurologic sequelae and a slight delay in neuro-motor development, the 2.5-year-old boy is in a healthy condition. This case demonstrates that hirudin can be an effective alternative anticoagulant in neonates and infants refractory to heparin treatment. Efficacy and safety issues of hirudin treatment, however, need to be evaluated in randomized trials.

[Analgesia for childbirth in a patient with factor V Leiden mutation]. / Analgesia para trabajo de parto en paciente con mutación del factor V Leiden.

Factor V Leiden mutation is the most common congenital thrombophilic disorder, affecting between 5% and 8% of the Caucasian population. Pregnancy creates a state of hypercoagulability and all factors that increase the risk of thrombosis should be considered, as they may be cumulative. In recent years, the diagnosis of new allelic variants of thrombophilic states have increased the incidence of pregnant women receiving anticoagulant therapy, with the anesthetic considerations that implies. We report the case of a 33-year-old woman with heterozygous Leiden factor V mutation who was admitted with spontaneous amniorrhexis in the 38th week of gestation. She was taking low molecular weight heparin therapy. An epidural catheter was inserted to provide analgesia for labor, with all safety precautions to prevent an epidural hematoma. Epidural anesthesia is the technique of choice for obstetric labor in patients with hypercoagulability because of its effects of favoring blood flow and inhibiting clot formation.

Analgesia para trabajo de parto en paciente con mutación del factor V Leiden / Analgesia for childbirth in a patient with Factor V Leiden mutation

La mutación del factor V Leiden, es la forma más frecuente de trastorno trombofílico congénito, afectando al 5-8% de la población caucasiana. La gestación supone, en sí misma, un estado de hipercoagulabilidad que nos debe llevar a prestar especial atención a todos aquellos factores de riesgo trombótico que puedan sumarse. En los últimos años, el diagnóstico de las nuevas variantes alélicas de los estados trombofílicos, ha incrementado la incidencia de gestantes que reciben anticoagulación con las consideraciones anestésicas que ello conlleva. Presentamos el caso de una mujer de 33 años de edad, portadora heterocigoto de una mutación en el gen del factor V Leiden, en tratamiento con heparina de bajo peso molecular, que ingresa por amniorrexis espontánea a la semana 38 de gestación. La paciente requirió analgesia para el trabajo de parto, por lo que se le colocó un catéter epidural cumpliendo los protocolos de seguridad y prevención del hematoma epidural. La anestesia epidural es la técnica de elección para analgesia del trabajo de parto, en las pacientes con hipercoagulabilidad, por sus efectos sobre la reología vascular y su efecto antitrombótico

Factor V Leiden mutation is the most common congenital thrombophilic disorder, affecting between 5% and 8% of the Caucasian population. Pregnancy creates a state of hypercoagulability and all factors that increase the risk of thrombosis should be considered, as they may be cumulative. In recent years, the diagnosis of new allelic variants of thrombophilic states have increased the incidence of pregnant women receiving anticoagulant therapy, with the anesthetic considerations that implies. We report the case of a 33-year-old woman with heterozygous Leiden factor V mutation who was admitted with spontaneous amniorrhexis in the 38th week of gestation. She was taking low molecular weight heparin therapy. An epidural catheter was inserted to provide analgesia for labor, with all safety precautions to prevent an epidural hematoma. Epidural anesthesia is the technique of choice for obstetric labor in patients with hypercoagulability because of its effects of favoring blood flow and inhibiting clot formation