scholarly journals Do Sexual Hormones Influence the Coagulation Parameters during the Normal Menstrual Cycle

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5047-5047
Author(s):  
Susan Halimeh ◽  
Hannelore Rott ◽  
Ihsan Osseiran ◽  
Guenther Kappert ◽  
Manuela Siebert
Keyword(s):  
Menstrual Cycle ◽  
Conflicts Of Interest ◽  
Oral Anticoagulants ◽  
Factor Vii ◽  
Blood Collection ◽  
Factor X ◽  
Sexual Hormones ◽  
Coagulation Parameters ◽  
Time Points ◽  
Normal Menstrual Cycle

Abstract Introduction: The blood coagulation can be influenced by different variables like mental stress, physical activity or oral anticoagulants. During the normal menstrual cycle changes have been observed on different time points. A study of Chaireti et al (1) found an association of progesterone and factor II, factor VII and factor X. We investigated the possible influence of the sexual hormones on the coagulation parameters. Samples and methods: We conducted a laboratory work group in 35 women sent to our lab. The following tests were conducted: Blood count, VWF:RCo, VWF:Ag, VWF:CB, Fibrinogen (Clauss), activities of FII, FV, FVII, FVIII (clotting and chromogenic), FIX, FX, FXI, FXII, FXIII, FSH, LH, Progesterone and Oestradiole during the menstrual cycle on predefined time points (day 1-6, day 7-11, day 12-18, day 19-23, day 24-28). Results: We found slight variations in nearly all coagulation parameters but without significance. The box-plots of the Von Willebrand activity shows that the means are relative close together. Clear variations could not be found. The Friedman-Test showed no significance. As expected the changes of the sexual hormones during the menstrual cycle showed highest significance. Conclusion: The influence of sexual hormones on coagulation parameters was not significant. The slight fluctuations may be caused by imprecision of the measurement and intra individual changes from day to day. Changes during the menstrual cycle could not be verified. Nevertheless it is advisable to investigate unclear negative results, when a conspicuous medical history or a corresponding clinic occurs. It is not necessary to regard the time point in the menstrual cycle for the blood collection. Literature: Chaireti R, Gustafsson KM, Byström B, Bremme K, Lindahl TL, Endogenous thromboin potential is higher during the luteal phase than during the follicular phase of a normal menstrual cycle, Hum Repro, 2013 Jul, 28 (7) 1846-52 Disclosures No relevant conflicts of interest to declare.

Changes Of Coagulation Parameters During The Menstrual Cycle

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4785-4785
Author(s):  
Susan Halimeh ◽  
Hannelore Rott ◽  
Guenther Kappert ◽  
Manuela Siebert
Keyword(s):  
Menstrual Cycle ◽  
Von Willebrand Disease ◽  
Factor Vii ◽  
Coagulation Disorder ◽  
Factor Xiii Deficiency ◽  
Coagulation Parameters ◽  
Time Points ◽  
Normal Menstrual Cycle ◽  
Cyclic Variations ◽  
Von Willebrand

Introduction Von Willebrand disease is the most common bleeding disorder with a prevalence of 1-2% of the population. Nevertheless diagnosis of a von Willebrand Syndrom Typ 1 is still challenging. In a newer publication (1), 30 studies about the haemostatic variables during the menstrual cycle were compared. 11 studies were focused on the von Willebrand parameters but only in one study these parameters in patients with von Willebrand disease were observed. We investigated possible cyclic variations in women with menorrhagia, which can lead to a diagnosis of a coagulation disorder. Samples and Methods We conducted a laboratory workup in 122 women sent to our lab for menorrhagia. The following tests were conducted: Blood count, VWF:RCo, VWF:Ag, VWF:CB, Fibrinogen (Clauss), activities of FII, FV, FVII, FVIII (clotting and chromogenic), FIX, FX, FXI, FXII, FXIII during the menstrual cycle on predefined time points (day 1-6, day 7-11, day 12-18, day 19-23, day 24-28). Results In 51 (40%) patients a von Willebrand disease could be detected, 37% hat other coagulation disorders like p. e. factor-VII-deficieny and factor-XIII-deficiency. 11.5% had an iron deficiency. In 11.5% no coagulation disorder could be found. In patients with von Willebrand disease we found cyclic variations especially in the VWF:Ag (p = 0.02). They showed the lowest level during the ovulation. For other coagulation parameters no significance for variations during the menstrual cycle were found. Conclusion There are cyclic variations in von Willebrand antigen. To investigate women on predefined time points during the menstrual cycle can be useful to diagnose a von Willebrand disease particularly in mild cases in which no other suspicious bleeding symptoms exists. Literature Knol H.M., Kemperman R.F.J., Kluin-Nelemans C., Mulder A.B., Meijer K., Haemostatic variables during normal menstrual cycle, Thrombosis and Haemostasis 107.1/2012 Disclosures: Halimeh: Octapharma AG: Investigator Other, Research Funding.

Does the menstrual cycle influence the sensitivity of vagally mediated baroreflexes?

2002 ◽  
Vol 102 (6) ◽  
pp. 639-644 ◽  
Author(s):  
William H. COOKE ◽  
David A. LUDWIG ◽  
Paul S. HOGG ◽  
Dwain L. ECKBERG ◽  
Victor A. CONVERTINO
Keyword(s):  
Menstrual Cycle ◽  
Young Women ◽  
Regulatory Mechanisms ◽  
Physiological Changes ◽  
Menstrual Cycles ◽  
Time Points ◽  
Normal Menstrual Cycle ◽  
Cardiac Regulation ◽  
Neck Pressure ◽  
Noradrenaline Levels

The menstrual cycle provokes several physiological changes that could influence autonomic regulatory mechanisms. We studied the carotid-cardiac baroreflex in ten healthy young women on four occasions over the course of their menstrual cycles (days 0-8, 9-14, 15-20 and 21-25). We drew blood during each session for analysis of oestrogen, progesterone and noradrenaline (norepinephrine) levels, and assessed carotid-cardiac baroreflex function by analysing R-R interval responses to graded neck pressure sequences. Oestrogen levels followed a classical two-peak (cubic) response, with elevated levels on days 9-14 and 21-25 compared with days 0-8 and 15-20 (P =0.0032), while progesterone levels increased exponentially from days 9-14 to days 21-25 (P = 0.0063). Noradrenaline levels increased from an average of 137pg/ml during the first three measurement periods to 199pg/ml during days 21-25 (P = 0.0456). Carotid-cardiac baroreflex gain and operational point were not statistically different at any of the time points during the menstrual cycle (P⩾0.18). These findings are consistent with the notion that beat-to-beat vagal-cardiac regulation does not change over the course of the normal menstrual cycle.

Clinical Implications of Crosstalk Between Coagulation and Inflammation: The Role of Anticoagulation in Treating Sepsis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2874-2874
Author(s):  
Zhi Xu ◽  
Elizabeth Phillips ◽  
Prasanta Basak ◽  
Stephen Jesmajian
Keyword(s):  
Vitamin K ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Vitamin K Antagonist ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Clinical Implications ◽  
Factor X ◽  
All Cause Mortality

Abstract BACKGROUND: Despite decades of active investigation, sepsis remains one of the leading causes of mortality worldwide. Multiple lines of evidence have illustrated that up-regulation of the activated Factor VII (FVIIa)/Tissue Factor (TF) complex, and its downstream extrinsic coagulation cascade, are major contributors to coagulopathies and inflammatory response during sepsis. For example, decreased mortality and inflammatory responses during sepsis were observed in mice with significantly reduced FVII expression. Another recent study demonstrated the association of increased mortality with higher levels of FVIIa in septic patients. Similar results have been demonstrated for Factor X (FX) and thrombin. In addition, several studies have been conducted to investigate the role of heparin in treating sepsis and have yielded promising results, however, the exact mechanisms remain elusive, and the clinical implications of crosstalk between coagulation pathways and sepsis are yet to be determined. Furthermore, the role of vitamin-K antagonist in sepsis has not been investigated. OBJECTIVE: To assess the effects of pre-existing anticoagulation with warfarin on the clinical course of septic patient. METHODS: This was a retrospective observational study undertaken in a community-based teaching hospital. Patients who were admitted with a primary diagnosis of sepsis from January 01 to June 30, 2012 were included in the study. The clinical characteristics between patient groups without and with prior anticoagulation were compared and analyzed. The primary outcomes include the severity of sepsis, length of hospitalization, and mortality rate during hospitalization. RESULTS: A total of 134 septic patients were included in the study. Among them, 105 patients were not anticoagulated, while 29 patients were anticoagulated, prior to admission (mean age: 76.0 + 1.2 vs. 77.5 + 2.6, p = 0.603). All of the patients with anticoagulation had been taking warfarin due to either pre-existing atrial fibrillation (79.3%) or deep vein thrombosis/pulmonary embolism (20.7%). There were significant differences in International Normalized Ratio (INR) of prothrombin time between groups without and with anticoagulation at the time of admission (1.28 + 0.04 vs. 4.59 + 0.83, p < 0.001). Septic patients who did not take warfarin prior to admission presented with higher Sepsis Indices (0.93 + 0.03 vs. 0.82 + 0.05, p < 0.05), resulting in longer hospitalizations (11.60 + 1.02 vs. 8.40 + 0.70, p < 0.001). The overall all-cause mortality rates during the hospitalization between patients without anticoagulation and those with anticoagulation were 23% vs. 14%, respectively. CONCLUSION: To our knowledge, this is the first study to demonstrate that septic patients with prior anticoagulation by a vitamin-K antagonist presented with less severity of sepsis, reduced length of hospital stay, and decreased all-cause mortality during hospitalization as compared with those without anticoagulation. In our study, prior administration of anticoagulation with warfarin may have had significant clinical implications in septic patients. This warrants further prospective studies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mathematical Modeling and Simulation Provides Evidence for New Strategies of Ovarian Stimulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Sophie Fischer ◽  
Rainald Ehrig ◽  
Stefan Schäfer ◽  
Enrico Tronci ◽  
Toni Mancini ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Menstrual Cycle ◽  
Ovarian Stimulation ◽  
Time Course ◽  
Scientific Evidence ◽  
Coupled Model ◽  
Continuous Growth ◽  
Time Points ◽  
Follicular Waves ◽  
Normal Menstrual Cycle

New approaches to ovarian stimulation protocols, such as luteal start, random start or double stimulation, allow for flexibility in ovarian stimulation at different phases of the menstrual cycle. It has been proposed that the success of these methods is based on the continuous growth of multiple cohorts (“waves”) of follicles throughout the menstrual cycle which leads to the availability of ovarian follicles for ovarian controlled stimulation at several time points. Though several preliminary studies have been published, their scientific evidence has not been considered as being strong enough to integrate these results into routine clinical practice. This work aims at adding further scientific evidence about the efficiency of variable-start protocols and underpinning the theory of follicular waves by using mathematical modeling and numerical simulations. For this purpose, we have modified and coupled two previously published models, one describing the time course of hormones and one describing competitive follicular growth in a normal menstrual cycle. The coupled model is used to test ovarian stimulation protocols in silico. Simulation results show the occurrence of follicles in a wave-like manner during a normal menstrual cycle and qualitatively predict the outcome of ovarian stimulation initiated at different time points of the menstrual cycle.

PROTEIN C RESPONSE TO INDUCTION AND WITHDRAWAL OF ORAL ANTICOAGULANT TREATMENT

1987 ◽  
Author(s):  
K P Schofield ◽  
J M Thomson ◽  
L Poller
Keyword(s):  
Oral Anticoagulant ◽  
Protein C ◽  
Oral Anticoagulants ◽  
Factor Vii ◽  
Factor X ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Rate Of Increase ◽  
Long Term Treatment

Protein C (PC) activity and antigen levels have been related to clotting activities of factors VII and X during the induction and withdrawal periods of oral anticoagulant treatment. Both factor VII and PC activities fell rapidly during a gradual induction regime of nicoumalone in six consecutive patients but factor VII showed a more rapid and much more marked depression than PC. In contrast reductions in factor X were much slower. PC antigen although depressed rapidly at the initiation of treatment did not subsequently fall to the same degree as PC activity, The ratio of activity to antigen became progressively smaller.In six further serial patients discontinued from long-term treatment with nicoumalone (mean duration 12-6 months) there was a reversal of the pattern, but with two important differences. Firstly, there was evidence of an excessive rise (“rebound”) of factor VII compared with the steady state levels in these patients; and secondly there was an unexpectedly slow return of PC activity and antigen to normal levels after the oral anticoagulant was withdrawn (levels were still below normal on day 4). Factor X also showed a slow rate of increase, similar to PC activity recovery. These observations lend support to gradual withdrawal of oral anticoagulants after a period of long-term administration. The results suggest that after discontinuation of long-term oral anticoagulants patients may have increased coagulability up to four days.

An Assessment Of An Amidolytic Assay For Factor VII In The Laboratory Control Of Oral Anticoagulants

1981 ◽  
Author(s):  
A Bodzenta ◽  
Jean M Thomson ◽  
Z S Latallo
Keyword(s):  
Prothrombin Time ◽  
Oral Anticoagulant ◽  
Oral Anticoagulants ◽  
Factor Vii ◽  
Limiting Factor ◽  
Factor X ◽  
Present Evidence ◽  
Chromogenic Assay ◽  
Better Than

An amidolytic assay for factor VII, modified from the method of Seligsohn et al (1978), has been compared with the results of the prothrombin time using British Comparative Thromboplastin, Thronbotest and a clotting assay for factor VII. In ‘long-term’ oral anticoagulant administration agreement with the conventional methods was good and better than in our previous study when amidolytic assays for factors II and X respectively were studied (Latallo et al 1981). The method appeared to be reasonably specific for factor VII.On the present evidence the chromogenic assay for factor VII offers a limited but apparently dependable guide to dosage but it is elaborate to perform and difficult to standardise. The main limiting factor for its routine application is the need to prepare a purified factor X extract.

COMPARISON OF HUMAN AND RABBIT BRAIN THROMBOPLASTIN IN THE EVALUATION OF LIVER DISEASE

1987 ◽  
Author(s):  
S Kitchen ◽  
R G Malia ◽  
D R Triger ◽  
M Greaves ◽  
F E Preston
Keyword(s):  
Liver Disease ◽  
Prothrombin Time ◽  
Oral Anticoagulants ◽  
Factor Vii ◽  
Rabbit Brain ◽  
Reference Laboratory ◽  
Factor V ◽  
Factor X ◽  
Time Data ◽  
Suitable Alternative

In the UK, rabbit brain thromboplastin has recently replaced human thromboplastin. Since the sensitivity of thromboplastin varies according to species of origin, and the calibration of thromboplastins is based entirely on samples from normal subjects and patients on oral anticoagulants, a separate assessment is required in patients with liver disease. We have compared prothrombin times and specific one stage assays of factors V, VII and X in plasma from 19 patients with establishe < liver disease using rabbit thromboplastin (Manchester reagent, MR) and human thromboplastin (Manchester comparative reagent, MCR). Both materials were kindly provided by the National (UK) Reference Laboratory for Anticoagulant Control. Three separate analyses were performed on the prothrombin time data viz clotting time, prolongation of prothrombin time compared with control and prothrombin ratio. All were significantly longer with MR (p 0.001, paired ‘t’ test) although correlation was goo< (r=0.95 in all instances).In the assay of factors V, VII and X no significant differences were obtained with the two thromboplastins and correlation was good over a range of abnormality (Ranges for MCR and MR respectively were Factor V:0.31-1.23u/ml and 0.32-1.I6u/ml, r=0.96; Factor VII:0.07-1.22u/ml and 0.07-1.17u/ml, r=0.97; Factor X;0.18-1.Olu/ml and 0.17-1.03u/ml, r=0.96. We conclude that in the investigation of the haemostatic defect associated with liver disease rabbit brain thromboplastin is a suitable alternative to human material.

Reversal of Novel Anticoagulants in Emergent Surgery and Trauma: A Comprehensive Review and Proposed Management Algorithm

2019 ◽  
Vol 24 (38) ◽  
pp. 4540-4553 ◽  
Author(s):  
Leonidas Palaiodimos ◽  
Jeremy Miles ◽  
Damianos G. Kokkinidis ◽  
Christos Barkolias ◽  
Anil K. Jonnalagadda ◽  
...  
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Oral Anticoagulants ◽  
Antibody Fragment ◽  
Thrombin Inhibitors ◽  
Factor Vii ◽  
Current Evidence ◽  
Factor X ◽  
Recombinant Activated Factor Vii ◽  
Reversal Agents ◽  
Emergent Surgery

Non-vitamin K oral anticoagulants (NOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, are increasingly used for thromboembolism prevention. Contrary to older anticoagulants, such as coumadin, when antidotes existed and were broadly used in cases of emergent surgery and bleeding, antidotes for NOACs have not been developed until recently. Moreover, the monitoring of NOAC’s anticoagulant effect varies across different hospital settings and the absence of a single test that can accurately predict the degree of anticoagulation achieved increases the uncertainty. These uncertainties often result in management dilemmas for clinicians when patients who are on NOACs need a reversal of anticoagulation. Until recently, available antidotes for NOACs included only prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII and the less optimal fresh frozen plasma (FFP). Recently though, novel antidotes for NOACs have been developed, including idarucizumab, which is a monoclonal antibody fragment that binds dabigatran, and andexanet alfa, a modified decoy form of the activated factor X (FXa) that binds FXa inhibitors and AT III. Another option, ciraparantag, which is a small molecule that binds to heparin, thrombin inhibitors and FXa inhibitors, is still in phase I development. In this review, we summarize the current evidence and present the available bypassing and novel reversal agents. Finally, we propose an algorithm for the management of patients who take NOACs and present to the emergency department with either trauma and active bleeding or need for emergent surgery.

scholarly journals Mathematical Models for the Prediction of Coagulation Activity in Patients with Paroxysmal Atrial Fibrillation

2020 ◽  
Vol 3 (2) ◽  
pp. 1-6
Keyword(s):  
Atrial Fibrillation ◽  
Linear Regression ◽  
Paroxysmal Atrial Fibrillation ◽  
Linear Regression Analysis ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor Xii ◽  
Factor X ◽  
Coagulation Activity ◽  
Coagulation Parameters

Our previous studies showed activation of coagulation in the early hours of the clinical manifestation of paroxysmal atrial fibrillation (PAF). Plasma coagulation activity of factor II, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XII, vWF, tissue factor levels, FVIII, vWF, prothrombin fragment 1+2(F1 + 2) and fibrinopeptide A (FPA) were significantly increased as early as the first twenty-four hours of the disease. The results suggest that there is a correlation between the studied parameters and development of the disease. Aim: To search for a statistical model that predicts coagulation activity in PAF patients. Materials and methods: Coagulation parameters were examined in 51 PAF patients (26 males, 25 females; mean age 59.84 ±1.60 years, onset of PAF episode < 24h prior to hospitalization). Controls included 52 individuals (26 males, 26 females; mean age 59.50 ± 1.46 years) with no prior anamnestic or ECG AF data, corresponding to patients in sex, age, BMI and comorbidities. A linear regression model was used to predict coagulation activity in PAF. Regression models showed good correlation between the duration of arrhythmia and six of the fourteen coagulation parameters studied: F1+2 (r = 0.83, p <0.001), FPA (r = 0.84, p <0.001), FVIII levels (r = 0.85, p <0.001) as well as activity of FII (r = 0.83, p <0.001), FVIII (r = 0.83, p <0.001) and FXII (r = 0.78, p <0.001). Changes in F1+2 plasma levels were most sensitive to PAF duration, where the contribution of duration to the values of the indicator is the greatest (b = 15.31). Conclusion: Linear regression analysis allowed us to create models with a high correlation coefficient for predicting the values of F1+2, FPA, FVIII levels, as well as activity of FII, FVIII and FXII in PAF patients. These models could allow for quantification of the procoagulatory process and thrombotic potential of the disease.

The Prevalence of Abnormal Coagulation Parameters in Patients with Newly Diagnosed Primary Systemic Amyloidosis and Its Impact on Outcome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5114-5114
Author(s):  
Tow Shung Tan ◽  
Angela Dispenzieri ◽  
Rajiv Pruthi ◽  
Martha Q. Lacy ◽  
Suzanne R. Hayman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Alkaline Phosphatase ◽  
Prothrombin Time ◽  
Light Chain ◽  
Systemic Amyloidosis ◽  
Factor Vii ◽  
Factor X ◽  
Newly Diagnosed ◽  
Coagulation Parameters ◽  
Hepatic Involvement

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder associated with varying degree of organ infiltration with light chain derived amyloid protein and consequent organ dysfunction. Various acquired coagulopathies, predominantly Factor X (FX) deficiency have been previously described in AL. The factor deficiencies are thought to be due to the direct binding of blood coagulation proteins to amyloid fibrils. Little is known regarding the prognostic significance of abnormal coagulation parameters in AL patients (pts). Methods: After Institutional Review Board approval, we performed a retrospective review of the medical records of 625 consecutive pts who had presented within 3 months of a diagnosis of AL to be evaluated at Mayo Clinic from June 2001 to June 2006. 540 pts had coagulation studies performed within 2 months of presentation. 51 of those pts were on oral anticoagulation and were excluded from the analysis. Results: Of the 489 pts included in the analysis, the median age was 62 years and 61% were male. The median overall survival (OS) of the entire cohort was 26.8 months. Table 1 lists the prevalence of abnormal coagulation tests in the remaining 489 patients. Prothrombin time (PT) was available in the majority of pts. 61 pts (12.6%) had elevated PT, and 63 pts (20.4%) had a decreased FX. 37 of the 61 pts with elevated PT had available FX levels, of which 31 (84%) of those had a decreased FX, suggesting that the cause of elevated PT was mostly due to a low FX. Indicators of hepatic involvement such as alkaline phosphatase and bilirubin levels were higher among the patients with prolonged PT and low FX. An elevated PT (more than 12.4 seconds) was strongly predictive of an adverse outcome, with a median OS of 8.7 months compared to a median OS of 29 months (p&lt;0.0001) in pts with normal PT (Figure 1). Similarly, pts with decreased FX (less than 60% activity), was associated with significantly worse outcomes with a median OS of 14.9 months versus a median OS of 33 months (p&lt;0.0001) in pts with normal FX (Figure 2). In a Cox proportional hazards model containing cardiac troponin (cTnT), NT-Pro BNP, serum alkaline phosphatase, and free light chain difference (involved minus uninvolved), prolonged PT or FX deficiency were independently prognostic for overall survival. Conclusion: Abnormalities of PT and FX are seen in a sizable proportion of pts with newly diagnosed AL. An elevated PT and or FX deficiency appear to adversely affect the outcome of these patients. It is likely that the elevated PT in these patients relate to FX deficiency in the majority which in turn may reflect the amyloid ‘burden’. The effect of other organ involvement like the hepatic involvement may also have an impact on FX and PT. Table 1. Prevalence of abnormal coagulation testing in patients with newly diagnosed primary systemic amyloidosis. Coagulation study N (Test results available) N of abnormal results (%) Elevated prothrombin time 486 61 12.6 Elevated activated partial thromboplastin time 312 48 15.4 Elevated thrombin time 315 84 26.7 Elevated fibrinogen 140 118 84.3 Decreased Factor II activity 62 26 41.9 Decreased Factor V activity 63 9 14.3 Decreased Factor VII activity 63 17 27 Decreased Factor X activity 309 63 20.4 Elevated D-dimer 130 72 55.4 Figure 1. Survival grouped by normal versus elevated Prothrombin time. Figure 1. Survival grouped by normal versus elevated Prothrombin time. Figure 2. Survival grouped by normal versus low Factor X levels. Figure 2. Survival grouped by normal versus low Factor X levels.

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