Isolated prolonged activated partial thromboplastin time in an asymptomatic patient: Fletcher factor deficiency

Background: Hereditary prekallikrein (Fletcher factor) deficiency is a rare condition characterized by a prolonged activated partial thromboplastin time. Inhibitors of plasma kallikrein have recently been approved for prophylaxis of hereditary angioedema and are under investigation for use in other indications. Objective: We attempted to conservatively assess the impact of long-term inhibition of this pathway by reviewing reported comorbidities in patients with hereditary prekallikrein deficiency. Methods: We searched several medical literature databases for publications that reported data from patients with hereditary prekallikrein deficiency (<10% of normal and/or shortening of activated partial thromboplastin time on increased incubation time). Data reporting of cardiovascular, bleeding, and autoimmune-related diseases were extracted. Results: Of 1966 publications screened, 45 publications (which represented 53 patients with prekallikrein deficiency) were included. Among 53 identified patients with prekallikrein deficiency, 25 were explicitly defined as asymptomatic, with no comorbidities mentioned in another three cases. Another 16 of the 53 patients were described as having undergone surgery or dental extractions with no complications. Cardiovascular comorbidities were reported in 19 patients, mainly hypertension (9 patients) and cerebrovascular ischemia or stroke (5 patients). Excessive bleeding episodes after surgery were reported in four patients. Autoimmune-related diseases were reported for three patients (two with Graves disease and one with systemic lupus erythematosus). Conclusion: This review identified patients with hereditary prekallikrein deficiency who reported a spectrum of health outcomes from asymptomatic to infrequent reports of cardiovascular, bleeding, and autoimmune comorbidities. The majority of the reports did not indicate any association between prekallikrein deficiency and comorbidities; however, additional observation is required to confirm the long-term safety of plasma kallikrein inhibition.

Download Full-text

Long-term safety outcomes of prekillikrein (Fletcher factor) deficiency: A systematic literature review of case reports

Allergy and Asthma Proceedings ◽

10.2500/aap.2019.40.190005 ◽

2019 ◽

Author(s):

Antonio Girolami ◽

Catherine Rolland ◽

Dan Sexton ◽

Moshe Vardi ◽

Jonathan A. Bernstein

Keyword(s):

Lupus Erythematosus ◽

Partial Thromboplastin Time ◽

Case Reports ◽

Activated Partial Thromboplastin Time ◽

Plasma Kallikrein ◽

Excessive Bleeding ◽

Factor Deficiency ◽

Fletcher Factor ◽

The Impact

Background: Hereditary prekallikrein (Fletcher factor) deficiency is a rare condition characterized by a prolonged activated partial thromboplastin time. Inhibitors of plasma kallikrein have recently been approved for prophylaxis of hereditary angioedema and are under investigation for use in other indications.Objective: We attempted to conservatively assess the impact of long-term inhibition of this pathway by reviewing reportedcomorbidities in patients with hereditary prekallikrein deficiency.Methods: We searched several medical literature databases for publications that reported data from patients with hereditaryprekallikrein deficiency (<10% of normal and/or shortening of activated partial thromboplastin time on increased incubationtime). Data reporting of cardiovascular, bleeding, and autoimmune-related diseases were extracted.Results: Of 1966 publications screened, 45 publications (which represented 53 patients with prekallikrein deficiency) wereincluded. Among 53 identified patients with prekallikrein deficiency, 25 were explicitly defined as asymptomatic, with no comorbidities mentioned in another three cases. Another 16 of the 53 patients were described as having undergone surgery or dental extractions with no complications. Cardiovascular comorbidities were reported in 19 patients, mainly hypertension (9 patients) and cerebrovascular ischemia or stroke (5 patients). Excessive bleeding episodes after surgery were reported in four patients. Autoimmune-related diseases were reported for three patients (two with Graves disease and onewith systemic lupus erythematosus).Conclusion: This review identified patients with hereditary prekallikrein deficiency who reported a spectrum of health outcomes from asymptomatic to infrequent reports of cardiovascular, bleeding, and autoimmune comorbidities. The majority of the reports did not indicate any association between prekallikrein deficiency and comorbidities; however, additional observation is required to confirm the long-term safety of plasma kallikrein inhibition.

Download Full-text

One-step chromogenic equivalent of activated partial thromboplastin time evaluated for clinical application

Clinical Chemistry ◽

10.1093/clinchem/37.7.1235 ◽

1991 ◽

Vol 37 (7) ◽

pp. 1235-1244 ◽

Cited By ~ 4

Author(s):

Gabriëlle E Ponjee ◽

Huib L Vader ◽

Net J de Wild ◽

Ger W T Janssen ◽

Fedde van der Graaf

Keyword(s):

Partial Thromboplastin Time ◽

Clinical Laboratory ◽

Intrinsic Factor ◽

Activated Partial Thromboplastin Time ◽

Factor Vii ◽

Factor Deficiency ◽

One Step ◽

The One

Abstract We evaluated the clinical usefulness of a recently developed semi-automated one-step chromogenic equivalent of activated partial thromboplastin time (APTT; Behring). This simple test is easily adaptable for automation. Generally, the results with this chromogenic one-step APTT were at least as precise as those obtained with comparative coagulometric methods. The chromogenic one-step APTT showed, both in vitro and in vivo, adequate sensitivity to congenital intrinsic factor deficiency but no sensitivity to Factor VII deficiency. Unlike a two-step coagulometric APTT (Dade), the one-step chromogenic APTT seemed sensitive to activation products of the contact system, which are present in immunoadsorbed factor-deficient plasma. The in vitro sensitivity of the chromogenic APTT to heparin was comparable with that of a coagulometric APTT, but the sensitivity to heparin in patients' samples differed slightly. The chromogenic APTT is relatively insensitive to anomalies in the fibrinogen-fibrin conversion. Finally, we observed discrepancies between the chromogenic and coagulometric APTT results for plasma of patients with disseminated intravascular coagulation. We conclude that this one-step chromogenic APTT warrants further evaluation for possible use as a routine test for the clinical laboratory.

Download Full-text

Update on the Clot Waveform Analysis

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029620912027 ◽

2020 ◽

Vol 26 ◽

pp. 107602962091202

Author(s):

Hideo Wada ◽

Takeshi Matsumoto ◽

Kohshi Ohishi ◽

Katsuya Shiraki ◽

Motomu Shimaoka

Keyword(s):

Differential Diagnosis ◽

Partial Thromboplastin Time ◽

Coagulation Factor ◽

Bleeding Risk ◽

Activated Partial Thromboplastin Time ◽

Waveform Analysis ◽

Factor Viii Activity ◽

Factor Deficiency ◽

Coagulation Factor Deficiency ◽

Low Levels

The activated partial thromboplastin time (APTT)–clot waveform analysis (CWA) was previously reported to be associated with the early detection of disseminated intravascular coagulation and was also reported to be able to measure very low levels of coagulation factor VIII activity. The software program for the analysis for the APTT-CWA allows the associated first and second derivative curves (first and second DCs) to be displayed. The first and second DC reflect the velocity and acceleration, respectively. The height of the first DC reflects the “thrombin burst” and bleeding risk, while that of the second DC is useful for detecting any coagulation factor deficiency and abnormal enhancement of coagulation by phospholipids. Activated partial thromboplastin time-CWA aids in making a differential diagnosis which is difficult to do using only the routine APTT. The CWA is currently used for many applications in the clinical setting, including the monitoring of hemophilia patients and patients receiving anticoagulant therapy and the differential diagnosis of diseases.

Download Full-text

Fletcher Factor Deficiency: Family Study and Detection

Blood ◽

10.1182/blood.v43.5.641.641 ◽

1974 ◽

Vol 43 (5) ◽

pp. 641-644 ◽

Cited By ~ 32

Author(s):

Charles F. Abildgaard ◽

Janet Harrison

Keyword(s):

Incubation Period ◽

Ellagic Acid ◽

Partial Thromboplastin Time ◽

Family Study ◽

Heterozygous State ◽

Factor Level ◽

Factor Production ◽

Factor Deficiency ◽

Fletcher Factor

Abstract Eight of 11 children of a known Fletcher factor-deficient individual were found to have normal activated partial thromboplastin times, normal levels of factors VIII, IX, XI, and XII, and a mean Fletcher factor level of 53% (range 40%-72%), suggesting a heterozygous state for the genecontrolling Fletcher factor production. All partial thromboplastin time reagents containing celite or kaolin were sensitive to Fletcher factor deficiency, while one reagent containing ellagic acid did not detect this abnormality. The finding of an abnormal partial thromboplastin time that is corrected by a 10-min incubation period is presumptive evidence for Fletcher factor deficiency.

Download Full-text

Patient’s Age and the Activated Partial Thromboplastin Time Test

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646757 ◽

1978 ◽

Vol 39 (03) ◽

pp. 780-781 ◽

Cited By ~ 4

Author(s):

Robert D Cawkwell

Keyword(s):

Partial Thromboplastin Time ◽

Activated Partial Thromboplastin Time ◽

Time Test

Download Full-text

Monitoring Heparin Therapy: Relationships between the Activated Partial Thromboplastin Time and Heparin Assays Based on Ex-Vivo Heparin Samples

Thrombosis and Haemostasis ◽

10.1055/s-0038-1645678 ◽

1990 ◽

Vol 63 (01) ◽

pp. 016-023 ◽

Cited By ~ 41

Author(s):

A M H P van den Bessekaar ◽

J Meeuwisse-Braun ◽

R M Bertina

Keyword(s):

Partial Thromboplastin Time ◽

Plasma Sample ◽

Ex Vivo ◽

Correlation Coefficients ◽

Heparin Therapy ◽

Thromboembolic Disease ◽

Activated Partial Thromboplastin Time ◽

Venous Thromboembolic Disease ◽

Venous Thromboembolic

SummaryFive different APTT reagents, two amidolytic anti-ITa assays, one amidoiytic anti-Xa assay, and one coagulometric anti-Xa/ anti-IIa assay were used to assess the effect of heparin in patients treated for venous thromboembolic disease. Good correlations were observed between lug-transformed APYE> determined with the various reagents (correlation coefficients: 0.92-0.96).Nevertheless there were important differences in the slopes of the lines of relationship between the APTT reagents.Good correlations were observed between the anti-Xa and anti-IIa assay results (correlation coefficients: 0.92-0.97). However, the amidolytic anti-Xa activity was significantly higher (p <0.001) than the two amidolytic anti-IIa activities. Less good correlations were observed between the log-transformed APTTs and the anti-Xa or anti-IIa activities (correlation coefficients: 0.64-0.78). The correlations were improved by transforming the APTT into APTT-ratio, i.e. the ratio of the patient’s APTT to the same patient’s APTT after removal of heparin from the plasma sample by means of ECTEOLA-cellulose treatment. The correlation coefficients of log (AFTT-ratio) with anti-Xa or anti-IIa ranged from 0.76 to 0.87.For both APTT and amidolytic heparin assay, the response to in vitro heparin was different from the response to ex vivo heparin.Therefore, equivalent therapeutic ranges should be assessed by using ex vivo samples rather than in vitro heparin. Because of the response differences between the APTT reagents, it is not adequate to define a therapeutic range for heparin therapy without specification of the reagent.

Download Full-text

Monitoring Anticoagulant Therapy by Activated Partial Thromboplastin Time: Hirudin Assessment

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648943 ◽

1994 ◽

Vol 72 (05) ◽

pp. 685-692 ◽

Cited By ~ 43

Author(s):

Michael T Nurmohamed ◽

René J Berckmans ◽

Willy M Morriën-Salomons ◽

Fenny Berends ◽

Daan W Hommes ◽

...

Keyword(s):

Whole Blood ◽

Partial Thromboplastin Time ◽

Ex Vivo ◽

Fold Increase ◽

Heparin Therapy ◽

Activated Partial Thromboplastin Time ◽

Recombinant Hirudin ◽

Interindividual Differences ◽

The Relationship

SummaryBackground. Recombinant hirudin (RH) is a new anticoagulant for prophylaxis and treatment of venous and arterial thrombosis. To which extent the activated partial thromboplastin time (APTT) is suitable for monitoring of RH has not been properly evaluated. Recently, a capillary whole blood device was developed for bed-side monitoring of the APTT and it was demonstrated that this device was suitable to monitor heparin therapy. However, monitoring of RH was not evaluated.Study Objectives. To evaluate in vitro and ex vivo the responsiveness and reproducibility for hirudin monitoring of the whole blood monitor and of plasma APTT assays, which were performed with several reagents and two conventional coagulometers.Results. Large interindividual differences in hirudin responsiveness were noted in both the in vitro and the ex vivo experiments. The relationship between the APTT, expressed as clotting time or ratio of initial and prolonged APTT, and the hirudin concentration was nonlinear. A 1.5-fold increase of the clotting times was obtained at 150-200 ng/ml plasma. However, only a 2-fold increase was obtained at hirudin levels varying from 300 ng to more than 750 ng RH/ml plasma regardless of the assays. The relationship linearized upon logarithmic conversion of the ratio and the hirudin concentration. Disregarding the interindividual differences, and presuming full linearity of the relationship, all combinations were equally responsive to hirudin.Conclusions. All assays were equally responsive to hirudin. Levels up to 300 ng/ml plasma can be reliably estimated with each assay. The manual device may be preferable in situations where rapid availability of test results is necessary.

Download Full-text

In Vitro Thrombogenicity Tests of Factor IX Concentrates

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657035 ◽

1979 ◽

Vol 42 (05) ◽

pp. 1355-1367 ◽

Cited By ~ 8

Author(s):

C V Prowse ◽

A Chirnside ◽

R A Elton

Keyword(s):

Factor Viii ◽

Partial Thromboplastin Time ◽

Generation Time ◽

Activated Partial Thromboplastin Time ◽

Factor Ix ◽

In Vitro Tests ◽

Factor Viii Inhibitor ◽

Factor Ixa ◽

Viii Inhibitor

SummaryVarious factor IX concentrates have been examined in a number of in vitro tests of thrombogenicity. The results suggest that some tests are superfluous as in concentrates with activity in any of these tests activation is revealed by a combination of the non-activated partial thromboplastin time, the thrombin (or Xa) generation time and factor VIII inhibitor bypassing activity tests. Assay of individual coagulant enzymes revealed that most concentrates contained more factor IXa than Xa. However only a small number of concentrates, chiefly those that had been purposefully activated, contained appreciable amounts of either enzyme.

Download Full-text