Risk of excessive bleeding associated with marginally low von Willebrand factor and mild platelet dysfunction

Abstract The safety, efficacy, and optimal dosing of a von Willebrand Factor/Factor VIII concentrate (Humate-P®) were evaluated in an open-label, uncontrolled study in patients with von Willebrand disease (VWD) undergoing elective surgery. During an initial pharmacokinetic (PK) phase, a detailed profile of FVIII:C, VWF:RCo, and VWF:AG was obtained for each patient after an infusion of 60 IU VWF:RCo/kg as Humate-P. Individual PK values were used to calculate subsequent loading and maintenance doses. Hemostatic efficacy was characterized using a 4-point scale (excellent, good, moderate/poor, or none) at several time points following surgery. Forty-two adults and children were enrolled in the study (17 VWD type 1; 6 type 2; 13 type 3; 6 type 2M), and 35 of these patients underwent a surgical procedure (classified as 3 oral, 7 minor, and 25 major). The median loading dose administered was 55.6 IU/kg (range 17.4 to 135.3 IU/kg). For patients with more severe VWD (baseline VWF:RCo<12 IU/dL), the median loading dose administered was 70.9 IU/kg (range 38.6 to 135.3 IU/kg). The dosing interval was 8 or 12 hours in most subjects (4 were dosed every 6 hours), and treatment duration ranged from 1 to 6 days depending on surgery type. Effective hemostasis (investigator- rated as “excellent” or “good”) was noted in 91.4% (32/35) of subjects immediately after surgery, 100% (35/35) of subjects 14 days after surgery, and 100% (34/34) of subjects evaluated 24 hours after the last infusion (primary endpoint). Mean blood loss was less than expected, and four patients required transfusions, related to their surgery. Only six adverse events were considered possibly treatment related: headache (3), itching, nausea, and dizziness (1). These results demonstrate that von Willebrand Factor/Factor VIII concentrate is safe and effective in the prevention of excessive bleeding during and after elective surgery in adult and pediatric patients with von Willebrand disease.

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M1761K mutation in the von Willebrand factor A3 domain associated with impaired collagen binding and without platelet dysfunction

Haemophilia ◽

10.1111/hae.12976 ◽

2016 ◽

Vol 22 (4) ◽

pp. e345-e346 ◽

Cited By ~ 1

Author(s):

D. M. Ong ◽

H. Aumann ◽

R. K. Andrews ◽

E. E. Gardiner ◽

S. E. Rodgers ◽

...

Keyword(s):

Von Willebrand Factor ◽

Platelet Dysfunction ◽

Collagen Binding ◽

Von Willebrand ◽

Willebrand Factor

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Covid-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

International Journal of Molecular Sciences ◽

10.3390/ijms21145168 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5168 ◽

Cited By ~ 12

Author(s):

Corlia Grobler ◽

Siphosethu C. Maphumulo ◽

L. Mireille Grobbelaar ◽

Jhade C. Bredenkamp ◽

Gert J. Laubscher ◽

...

Keyword(s):

Endothelial Cells ◽

Von Willebrand Factor ◽

Poor Prognosis ◽

Point Of Care ◽

Signalling Pathways ◽

Platelet Dysfunction ◽

Multiple Risk Factors ◽

Von Willebrand ◽

Willebrand Factor ◽

D Dimer

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), also known as coronavirus disease 2019 (COVID-19)-induced infection, is strongly associated with various coagulopathies that may result in either bleeding and thrombocytopenia or hypercoagulation and thrombosis. Thrombotic and bleeding or thrombotic pathologies are significant accompaniments to acute respiratory syndrome and lung complications in COVID-19. Thrombotic events and bleeding often occur in subjects with weak constitutions, multiple risk factors and comorbidities. Of particular interest are the various circulating inflammatory coagulation biomarkers involved directly in clotting, with specific focus on fibrin(ogen), D-dimer, P-selectin and von Willebrand Factor (VWF). Central to the activity of these biomarkers are their receptors and signalling pathways on endothelial cells, platelets and erythrocytes. In this review, we discuss vascular implications of COVID-19 and relate this to circulating biomarker, endothelial, erythrocyte and platelet dysfunction. During the progression of the disease, these markers may either be within healthy levels, upregulated or eventually depleted. Most significant is that patients need to be treated early in the disease progression, when high levels of VWF, P-selectin and fibrinogen are present, with normal or slightly increased levels of D-dimer (however, D-dimer levels will rapidly increase as the disease progresses). Progression to VWF and fibrinogen depletion with high D-dimer levels and even higher P-selectin levels, followed by the cytokine storm, will be indicative of a poor prognosis. We conclude by looking at point-of-care devices and methodologies in COVID-19 management and suggest that a personalized medicine approach should be considered in the treatment of patients.

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COVID-19: The Rollercoaster of Fibrin(ogen), D-dimer, von Willebrand Factor, P-selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

10.20944/preprints202007.0142.v1 ◽

2020 ◽

Author(s):

Corlia Grobler ◽

Jhade Bredenkamp ◽

Mireille Grobbelaar ◽

Sipho Maphumulo ◽

Jaco Laubscher ◽

...

Keyword(s):

Endothelial Cells ◽

Von Willebrand Factor ◽

Poor Prognosis ◽

Point Of Care ◽

Platelet Dysfunction ◽

Multiple Risk Factors ◽

Low Levels ◽

Von Willebrand ◽

Willebrand Factor ◽

D Dimer

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), coronavirus disease 2019 (COVID-19)-induced infection is strongly associated with various coagulopathies that may result in either bleeding and thrombocytopenia or hypercoagulation and thrombosis. Thrombotic and bleeding or thrombotic pathologies are significant accompaniments to acute respiratory syndrome and lung complications in COVID-19. Thrombotic events and bleeding, often occurs in subjects with weak multiple risk factors and co-morbidities. Of particular interest are the various circulating inflammatory coagulation biomarkers involved directly in clotting, with specific focus on fibrin(ogen), D-dimer, P-selectin and von Willebrand Factor (vWF). Central to activity of these biomarkers are their receptors and signaling pathways on endothelial cells, platelets and erythrocytes. In this review, we discuss vascular implications of COVID-19, and relate this to circulating biomarker, endothelial, erythrocyte and platelet dysfunction. During the progression of the disease, these markers may either be within healthy levels, upregulated or eventually depleted. Most significant is that patients need to be treated early in the disease progression, when high levels of vWF, P-selectin and fibrinogen are present with still low levels of D-dimer. Progression to vWF and fibrinogen depletion with high D-dimer levels and even higher P-selectin levels, followed by the cytokine storm, will be indicative of a poor prognosis. We conclude by looking at point-of-care devises and methodologies in COVID-19 management and suggest that a personalized medicine approach should be considered in the treatment of patients.

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Transfusion Requirements Are Correlated with the Degree of Proteolysis of von Willebrand Factor during Orthotopic Liver Transplantation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657634 ◽

1997 ◽

Vol 78 (02) ◽

pp. 813-819 ◽

Cited By ~ 6

Author(s):

A Lattuada ◽

P M Mannucci ◽

C Chen ◽

C Legnani ◽

G Palareti

Keyword(s):

Liver Transplantation ◽

Orthotopic Liver Transplantation ◽

Von Willebrand Factor ◽

Bleeding Tendency ◽

Excessive Bleeding ◽

Transfusion Requirements ◽

Activity Of Enzymes ◽

Von Willebrand ◽

Willebrand Factor

SummaryDuring orthotopic liver transplantation (OLT) excessive bleeding is the main cause of death and graft failure. The acute bleeding tendency that accompanies OLT, particularly during the anhepatic period and after reperfusion of the graft, is due to the depletion or functional abnormalities of several hemostasis components caused by the enhanced activity of enzymes such as plasmin, trypsin and leukocyte proteases. We surmised that enhanced proteolysis might also cause abnormalities of von Willebrand factor (vWF), and that these abnormalities are implicated in the bleeding tendency that develops during OLT. Therefore, the pattern of vWF proteolysis was studied with 16 patients with chronic liver disease, in serial blood samples obtained before OLT, during the anhepatic stage, after graft reperfusion and at the end of the surgical procedure. vWF became markedly degraded during the anhepatic and reperfusion stages, as shown by the partial loss of high molecular weight multimers, the relative decrease of the intact 225 kD subunit and the increase of the native proteolytic fragments of 176 and 140 kD. Novel proteolytic fragments also became detectable. Using monoclonal antibody epitope mapping, it could be demonstrated that some of the proteolytic fragments corresponded in apparent molecular mass to those produced in vitro by incubating purified vWF with plasmin or elastase, but other fragments could not be attributed to these proteases. During the anhepatic and reperfusion stages there was a significant correlation between the degree of vWF degradation and the total amount of blood components transfused to replace blood losses. To evaluate whether or not vWF degradation could be controlled by the administration of a broad-spectrum protease inhibitor such as aprotinin, 5 patients were given a bolus dose of 500,000 U before surgery followed by 100,000 U/h during surgery, 5 were given a 2,000,000 U bolus followed by 500,000 U/h, and no aprotinin was given to the remaining 6 patients. There were no differences in the patterns or degrees of vWF degradation between patients treated with aprotinin or not. In conclusion, there is a marked degradation of a key hemostasis protein during OLT. These alterations may be of clinical significance, because they are correlated with the transfusion requirements.

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A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interaction

Blood ◽

10.1182/blood.v75.1.20.20 ◽

1990 ◽

Vol 75 (1) ◽

pp. 20-26 ◽

Cited By ~ 101

Author(s):

C Mazurier ◽

J Dieval ◽

S Jorieux ◽

J Delobel ◽

M Goudemand

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Laboratory Data ◽

Bleeding Diathesis ◽

Excessive Bleeding ◽

New Variant ◽

History Of ◽

Von Willebrand ◽

Willebrand Factor

Abstract The patients with inherited bleeding diathesis related to quantitative, structural, and/or functional abnormalities of von Willebrand factor (vWF) are said to have von Willebrand's disease (vWD). We report here the clinical and laboratory features of a 50-year-old woman with a life- long history of excessive bleeding. Her particular laboratory data are factor VIII (FVIII) deficiency, subnormal bleeding time, and the presence of all plasma and platelet vWF multimers in normal amounts. Infused with FVIII/vWF concentrate, she showed a persistent increase in FVIII that led us to discard hemophilia A carrier or “acquired hemophilia” diagnoses. vWF devoid of FVIII purified from normal and patient's plasma by immunoaffinity on anti-vWF monoclonal antibody (MoAb) was immobilized onto polystyrene tubes that were further incubated with purified normal FVIII. The bound FVIII was evidenced using radiolabeled anti-FVIII MoAb. The data showed that the patient's vWF, in contrast to vWF purified from normal plasma, was unable to bind FVIII. Furthermore, no inhibitor of FVIII/vWF interaction was evidenced in incubating purified normal vWF with the patient's plasma before the addition of FVIII and anti-FVIII MoAb. These results support the concept that the bleeding diathesis of this patient appears to be due mainly to her abnormal vWF preventing FVIII/vWF interaction. This abnormality, which is not yet described in present classification of vWD, could be considered as a new variant of vWD.

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Efficacy of factor VIII/von Willebrand factor concentrate Alphanate®in preventing excessive bleeding during surgery in subjects with von Willebrand disease

Haemophilia ◽

10.1111/j.1365-2516.2007.01616.x ◽

2008 ◽

Vol 14 (2) ◽

pp. 271-275 ◽

Cited By ~ 27

Author(s):

G. E. RIVARD ◽

L. ALEDORT ◽

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Von Willebrand Disease ◽

Excessive Bleeding ◽

Factor Concentrate ◽

Von Willebrand ◽

Willebrand Factor

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A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interaction

Blood ◽

10.1182/blood.v75.1.20.bloodjournal75120 ◽

1990 ◽

Vol 75 (1) ◽

pp. 20-26

Author(s):

C Mazurier ◽

J Dieval ◽

S Jorieux ◽

J Delobel ◽

M Goudemand

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Laboratory Data ◽

Bleeding Diathesis ◽

Excessive Bleeding ◽

New Variant ◽

History Of ◽

Von Willebrand ◽

Willebrand Factor

The patients with inherited bleeding diathesis related to quantitative, structural, and/or functional abnormalities of von Willebrand factor (vWF) are said to have von Willebrand's disease (vWD). We report here the clinical and laboratory features of a 50-year-old woman with a life- long history of excessive bleeding. Her particular laboratory data are factor VIII (FVIII) deficiency, subnormal bleeding time, and the presence of all plasma and platelet vWF multimers in normal amounts. Infused with FVIII/vWF concentrate, she showed a persistent increase in FVIII that led us to discard hemophilia A carrier or “acquired hemophilia” diagnoses. vWF devoid of FVIII purified from normal and patient's plasma by immunoaffinity on anti-vWF monoclonal antibody (MoAb) was immobilized onto polystyrene tubes that were further incubated with purified normal FVIII. The bound FVIII was evidenced using radiolabeled anti-FVIII MoAb. The data showed that the patient's vWF, in contrast to vWF purified from normal plasma, was unable to bind FVIII. Furthermore, no inhibitor of FVIII/vWF interaction was evidenced in incubating purified normal vWF with the patient's plasma before the addition of FVIII and anti-FVIII MoAb. These results support the concept that the bleeding diathesis of this patient appears to be due mainly to her abnormal vWF preventing FVIII/vWF interaction. This abnormality, which is not yet described in present classification of vWD, could be considered as a new variant of vWD.

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Laboratory Response to Intranasal Desmopressin in Women with Menorrhagia and Underlying Platelet Dysfunction.

Blood ◽

10.1182/blood.v110.11.3201.3201 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3201-3201

Author(s):

Shelonitda S. Rose ◽

Ambarina Faiz ◽

Connie H. Miller ◽

Parvin Saidi ◽

Claire S. Philipp

Keyword(s):

Blood Flow ◽

Platelet Aggregation ◽

Von Willebrand Factor ◽

Atp Release ◽

Menstrual Blood ◽

Platelet Dysfunction ◽

Closure Time ◽

Intranasal Desmopressin ◽

Von Willebrand ◽

Willebrand Factor

Abstract Intranasal desmopressin (IN-DDAVP) is used for home treatment of menorrhagia in women with inherited bleeding disorders. The effect of IN-DDAVP on laboratory hemostatic parameters in women with menorrhagia and associated platelet dysfunction is unknown. We evaluated the effects of IN-DDAVP on hemostatic parameters in women with menorrhagia and platelet dysfunction and correlated them with menstrual blood flow. Eleven women (aged 18–45) with menorrhagia and abnormal platelet aggregation and/or platelet adenosine tri-phosphate (ATP) release had determination of factor VIII coagulant activity (FVIII: C), von Willebrand factor antigen (VWF: Ag), von Willebrand factor ristocetin cofactor (VWF: RCo) activity, platelet aggregation, and platelet ATP release pre and 60 minutes post IN-DDAVP. Eight of eleven women underwent Platelet Function Analyzer (PFA-100) closure time determination with collagen/epinephrine (CEPI) and collagen/adenosine diphosphate (CADP) cartridge pre and post treatment. IN-DDAVP was administered during two consecutive menstrual cycles. Menstrual blood flow was assessed during each cycle using a pictorial blood assessment chart (PBAC). Following administration of IN-DDAVP there was a 2–3 fold increase in FVIII: C, VWF: Ag, and VWF: RCo observed in most patients over baseline levels. Mean FVIII:C increased from 130% ± 34.8% to 218% ± 96.5% (P < 0.007), VWF: Ag increased from 86.9% ± 35.1% to 128.7% ± 64.3% (P < 0.011), and VWF: RCo increased from 89.8% ± 42.8% to 139.6% ± 86.5% (P < 0.02). The median baseline PBAC score of 235 decreased to 136 following IN-DDAVP. In addition, there were significant inverse correlations between changes in PBAC score and changes in VWF: Ag (rs = − 0.85, p = 0.02), VWF: RCo (rs = −0.81, p = 0.029), and FVIII:C (rs = 0.92, p = 0.003) with IN-DDAVP. Mean PFA-100 closure time with the CEPI cartridge shortened from 166.8sec ± 85sec to 90.9sec ± 49.3sec (p< 0.02), and the closure time with the CADP cartridge shortened from 104.5sec ± 34.3sec to 64.8sec ± 40.4sec (p <0.007). There were significant inverse correlations between post IN-DDAVP PFA-100 CADP closure time and post IN-DDAVP FVIII:C (rs = −0.86, p = 0.005), VWF: Ag (rs = −0.72, p = 0.04), and VWF: RCo (rs = −0.80, p = 0.01). In addition there were also significant inverse correlations between post IN-DDAVP PFA-100 CEPI closure time and post IN-DDAVP FVIII:C (rs = −0.73, p = 0.03), and VWF: RCo (rs = −0.74, p = 0.03), but not VWF: Ag (rs = −0.66, p = 0.07). In-vitro platelet aggregation and platelet ATP release response did not correct and did not correlate with changes in menstrual blood flow. Our results demonstrate a correlation between VWF parameters and menstrual blood flow following IN-DDAVP in women with menorrhagia and underlying platelet dysfunction.

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