scholarly journals The remarkable diversity of thrombotic thrombocytopenic purpura: a perspective

2018 ◽  
Vol 2 (12) ◽  
pp. 1510-1516 ◽  
Author(s):  
James N. George
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Immunosuppressive Treatment ◽  
Severe Thrombocytopenia ◽  
Adamts13 Activity ◽  
Long Term Outcomes ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Few Data ◽  
Autoimmune Etiology

Abstract Understanding the autoimmune etiology of acquired thrombotic thrombocytopenic purpura (TTP) has provided precision for the diagnosis and a rationale for immunosuppressive treatment. These advances have also allowed recognition of the remarkable clinical diversities of patients’ initial presentations and their long-term outcomes. These diversities are illustrated by the stories of patients from the Oklahoma TTP Registry. The initial presentation of TTP may be the discovery of unexpected severe thrombocytopenia in a patient with minimal or no symptoms. The patient may remain asymptomatic throughout treatment or may die suddenly before treatment can be started. ADAMTS13 activity may be reported as normal in a patient with characteristic clinical features of TTP, or the unexpected report of ADAMTS13 deficiency in a patient with another established disorder may lead to the discovery of TTP. ADAMTS13 activity during clinical remission is unpredictable. ADAMTS13 activity may recover and remain normal, it may remain severely deficient for many years, or it may become normal only many years after recovery. Our treatment of initial episodes and management of patients after recovery and during remission continue to change. The addition of rituximab to the treatment of acute episodes and preemptive rituximab for patients with severe ADAMTS13 deficiency during remission are reported to prevent relapse. Because TTP is uncommon, there are few data to guide these changes. Therefore our patients’ stories are profoundly influential. Their stories are the foundation of our experience, and our experience is the guide for our decisions.

scholarly journals Complement Activation May Trigger the Onset of Thrombotic Thrombocytopenic Purpura in Patients with Severe ADAMTS13 Deficiency

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 600-600 ◽  
Author(s):  
Xiao-Hui Hu ◽  
Jialing Bao ◽  
Yoshiyasu Ueda ◽  
Takashi Miwa ◽  
Wenchao Song ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Complement Activation ◽  
Factor H ◽  
Severe Thrombocytopenia ◽  
Complement Factor ◽  
Healthy Controls ◽  
Adamts13 Activity ◽  
Activation Markers ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Thrombotic thrombocytopenic purpura (TTP), a potential fatal syndrome, is often associated with severe deficiency of plasma ADAMTS13 activity, either resulting from ADAMTS13 mutations or acquired anti-ADAMTS13 autoantibodies that inhibit plasma ADAMTS13 activity. Patients with severe ADAMTS13 do not always have TTP signs and symptoms, which often occur following infections or inflammatory responses. The mechanism of TTP flare is not fully understood. In the present study, complement activation markers (iC3b, C5b, Bb, and C4b) were determined by enzyme-linked absorbent assays (ELISA) in the initial plasmas (prior to plasma exchange) of 20 patients with acquired TTP with severe ADAMTS13 deficiency (less than 20% of normal) and plasmas from 20 healthy controls. Of 20 TTP patients, 19 exhibited positive inhibitor in the 50:50 mixing study. Plasma levels of iC3b (1,000 ± 1,062 ng/ml), sC5b-9 (1,342±867 ng/ml), and Bb (38.2±47.7 ng/ml), as well as C4b (74.3±49.5 ng/ml) in acquired TTP patients were significantly higher than those in healthy controls (p value less than 0.01) These results indicate that complement activation in both classic and alternative pathways is a common phenomenon in patients with acquired autoimmune TTP. To demonstrate the causative effect of complement activation in TTP, we turned to our Adamts13 null mice. C57BL/6 (Adamts13-/-) mice are resistant to the development of spontaneous and Shigatoxin-induced TTP syndrome. When injected with a murine specific monoclonal antibody against complement factor H (CFH) (800 micro grams/mouse), which inhibits binding of circulating CFH to endothelial cells and C3b, Adamts13-/- mice (C57BL/6) developed more severe thrombocytopenia and anemia than wild type mice did within 6 days without additional challenge. However, renal insufficiency manifested by the increase of plasma BUN concentration was similar in both groups (Fig. 1). These results indicate that complement activation through an alternative pathway, following antibody-mediated inhibition of CFH or other complement regulatory components, may trigger the onset of TTP in light of severe ADAMTS13 deficiency. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Clinical and Outcomes Findings for Thrombotic Thrombocytopenic Purpura among 467 Persons with Severely Versus Not Severely Deficient ADAMTS-13 Levels.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2088-2088 ◽  
Author(s):  
Charles L. Bennett ◽  
Thanh Ha Luu ◽  
Anaadriana Zakarija ◽  
Hau C. Kwaan ◽  
Nicholas Bandarenko ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Neutralizing Antibodies ◽  
Clinical Laboratory ◽  
Survival Rates ◽  
Outcome Data ◽  
Severe Thrombocytopenia ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that presents with microangiopathic hemolytic anemia and thrombocytopenia, fevers, renal insufficiency and neurologic features. We reviewed clinical, laboratory, and outcome data for TTP cases with severely deficient versus non-severely deficient ADAMTS13 activity levels. Methods: Mean and median data were from the Surveillance, Epidemiology and Risk Factors for TTP (SERF-TTP) study group for idiopathic TTP cases, the Canadian Apheresis Group (CAG), and five published series (Zheng 2004, Raife 2004, Vesely 2003 (Oklahoma TTP-HUS Registry), Matsumoto 2004 (Japan Referral Center), Bennett 2007). Results: Compared to TTP cases with near-normal ADAMTS13 activity levels (n= 282), TTP cases with severe ADAMTS13-deficiency (n=185) were more likely to have severe thrombocytopenia, normal renal function and neutralizing ADAMTS13 antibodies. Severe ADAMTS13 deficient TTP cases have better overall survival after therapeutic plasma exchange (TPE) but are more likely to relapse. TTP patients with severe ADAMTS13 deficiency were primarily categorized as idiopathic or ticlopidine-associated, while TTP patients with non-severely deficient ADAMTS13 activity levels were frequently categorized as idiopathic, secondary to drugs (clopidogrel, quinine), stem cell transplantation, or cancer. Conclusions: Severe ADAMTS13 deficiency is most commonly idiopathic, has better survival following TPE, and a 35–40% spontaneous relapse rate. By contrast, non-ADAMTS13 deficient TTP cases are usually associated with an underlying disorder or external insults. Amongst this cohort, four series have 47–62% survival rates and three series, which contain mostly idiopathic cases, have 83–90% survival rates following TPE. From this, we propose that TTP may occur by three possible mechanism; ADAMTS13-deficient (antibody-mediated), an immunologic mediated pathway independent of ADAMTS13 (i.e. quinine) that is responsive to TPE, and endothelial injury related TTP that is unresponsive to TPE. Platelet count mean (x10^9/L) Creatinine mean (mg/dl) ADAMTS13 neutralizing antibodies (%) Survival % Relapse % * <15% ADAMTS13 activity cutoff Severe ADAMTS13 Deficiency (<10–15%) SERF-TTP (n=30) 19 1.3 83 97 41 Zheng (n=16) 19 1.6 44 81 38 Bennett (n=26) 15 85 Oklahoma (n=18) 12 1.8 94 81 38 Raife (n=50) * 13 1.2 92 35 Japan (n=34) 35 91 Canada (n=11) 16 2.4 82 Not Severely Deficient ADAMTS13 Activity (> 15%) SERF-TTP (n=22) 57 3.9 35 90 0 Raife (n=57) * 44 2.7 83 9 Canada (n=17) 57 4.1 88 Zheng (n=13) 40 3.0 0 54 Bennett (n=13) 62 Japan (n=66) 9 62 Oklahoma (n=94 ) 23 47 3

scholarly journals Diagnostic and therapeutic challenges in the thrombotic thrombocytopenic purpura and hemolytic uremic syndromes

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 604-609 ◽  
Author(s):  
James N. George ◽  
Zayd L. Al-Nouri
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Clinical Features ◽  
Clinical Decision ◽  
Response To Treatment ◽  
Long Term Outcomes ◽  
Thrombocytopenic Purpura ◽  
Long Term Follow Up ◽  
Adamts13 Deficiency

Abstract Evaluation and management of patients with suspected thrombotic thrombocytopenic purpura (TTP) continue to be a critical challenge for hematologists. The diagnostic criteria are not precise, often causing uncertainty about whether it is appropriate to initiate plasma exchange (PEX), the essential treatment for TTP. Initiation of PEX remains a clinical decision; severe ADAMTS13 (< 10% activity) deficiency alone is neither sufficiently sensitive nor specific for the diagnosis of TTP. However, patients who do have severe acquired ADAMTS13 deficiency define the characteristic clinical features of TTP, the response to treatment, and the long-term outcomes. Patients with severe acquired ADAMTS13 deficiency are predominantly young women and the relative frequency of blacks is increased. Patients may present with only microangiopathic hemolytic anemia and thrombocytopenia, neurologic and renal abnormalities are often not present, fever rarely occurs; the complete “pentad” of these clinical features almost never occurs in current practice. Response to PEX is typically rapid but may not be sustained when PEX is stopped. Use of corticosteroids and rituximab has decreased the number of PEX treatments required to achieve a remission and has resulted in fewer PEX-related major complications. Relapse (in approximately 40% of patients) may be the most apparent risk after recovery, but long-term health outcomes are also very important. Minor cognitive abnormalities are common, the frequency of depression is increased, and the frequency of hypertension is increased. Careful long-term follow-up of TTP patients is essential.

scholarly journals Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015

2017 ◽  
Vol 1 (10) ◽  
pp. 590-600 ◽  
Author(s):  
Evaren E. Page ◽  
Johanna A. Kremer Hovinga ◽  
Deirdra R. Terrell ◽  
Sara K. Vesely ◽  
James N. George
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Diagnostic Criteria ◽  
Kidney Function ◽  
Clinical Judgment ◽  
Adamts13 Activity ◽  
Long Term Outcomes ◽  
Thrombocytopenic Purpura ◽  
Key Points ◽  
Seriously Ill

Key Points The diagnosis of TTP requires clinical judgment in addition to measurement of ADAMTS13 activity. Patients with TTP may not seem to be seriously ill; they may have no or only mild neurologic and kidney function abnormalities.

scholarly journals Exome Sequencing Identifies Glycosylation Defects As a Probable Cause of Immune Thrombotic Thrombocytopenic Purpura

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 217-217
Author(s):  
Felipe Massicano ◽  
Elizabeth M. Staley ◽  
Konstantine Halkidis ◽  
Nicole K. Kocher ◽  
Lance A. Williams ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Potential Contribution ◽  
Severe Thrombocytopenia ◽  
Adamts13 Activity ◽  
Genomic Alterations ◽  
Autoantibody Production ◽  
Thrombocytopenic Purpura ◽  
Long Term Outcome ◽  
Clinical Presentations

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal syndrome, resulting primarily from autoantibodies against ADAMTS13. However, the mechanism underlying the autoantibody formation and the contribution of other genomic alterations to the pathogenesis of iTTP are largely unknown. Methods: Whole exome sequencing (WES) and bioinformatic analyses were performed to determine the genetic variations in 40 patients with iTTP who had ADAMTS13 activity &lt;10 IU/dL and a positive inhibitor or an elevated anti-ADAMTS13 IgG in concordance with clinical presentations of severe thrombocytopenia and microangiopathic hemolytic anemia with various degrees of organ injury. WES was also performed at the same time in fifteen age-, gender-, and ethnicity- matched individuals who did not have a history of iTTP or other hematological disorders as controls. Results: WES identified variants or mutations in the genes involving in glycosylation, including O-linked glycosylation, to be the major pathway affected in patients with iTTP. We propose that the altered glycosylation may be responsible for the development of autoantibodies against ADAMTS13 which impair the proteolytic cleavage of von Willebrand factor, accelerate the clearance of ADAMTS13 from circulation, and result in severe thrombocytopenia platelets in patients with iTTP. We also identified defects in ankyrin repeat containing protein ANKRD36C, a protein with hitherto unknown function, as the most statistically significant genomic alterations associated with iTTP (p &lt; 10-5). Moreover, candidate gene analysis revealed that various genes involving in hemostasis, complement activation, platelet function and signaling pathway, and inflammation were all affected in patients with iTTP, which may contribute to the onset, progress, severity, and long-term outcome of iTTP. Finally, we also identified two patient subgroups where the disease mechanism might be different. Conclusion: Our findings provide novel insight into the pathogenic mechanism underlying ADAMTS13 autoantibody production and the potential contribution of other genetic abnormalities in modifying the iTTP clinical presentations in the individuals with severe deficiency of plasma ADAMTS13 activity. Disclosures Zheng: Alexion: Speakers Bureau; Ablynx/Sanofi: Consultancy, Speakers Bureau; Shire/Takeda: Research Funding; Clotsolution: Other: Co-Founder.

Risk Factors for Recurrence of Thrombotic Thrombocytopenic Purpura.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1060-1060 ◽  
Author(s):  
Flora Peyvandi ◽  
Silvia Lavoretano ◽  
Roberta Palla ◽  
Hendrik B. Feys ◽  
Tullia Battaglioli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Relative Risk ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Recurrence ◽  
Acute Episode ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Neutralizing Activity ◽  
Adamts13 Deficiency

Abstract The introduction of plasma exchange therapy in early 1970s significantly reduced the rate of mortality in patients affected by thrombotic thrombocytopenic purpura (TTP), a disease characterized by thrombocytopenia and microangiopathic hemolytic anemia. A similar improvement was never achieved in the prevention of the disease recurrence. Still, 20–50% of patients, who survived the fatal disease, experience a relapse one month or even years after the acute episode of TTP. There is no pathognomic marker or laboratory test that can be used for the surveillance of TTP during remission and predict which patients will relapse. We have retrospectively analyzed for the first time at remission the role of ADAMTS13, anti-ADAMTS13 autoantibodies and von Willebrand Factor (VWF) in 109 patients who survived the acute episode of TTP. ADAMTS13 activity and ADAMTS13 antigen levels were measured as described by Gerritsen et al (TH 1999) and Feys HB et al. (JTH 2006), respectively. The total anti-ADAMTS13 autoantibodies (with and without neutralizing activity) were measured by western blot analysis and the presence of neutralizing anti-ADAMTS13 autoantibodies was checked according to Gerritsen et al (TH 1999). VWF antigen was measured using an ELISA assay and VWF multimers analysis was carried out using low-resolution SDS-agarose gel electrophoresis and exposing gels to human anti-VWF antibodies labeled with I125 for autoradiography (Ruggeri & Zimmerman, Blood 1981). All variables have been statistically analyzed in 2 subgroups of patients with or without TTP recurrence, in order to understand the role of each variable as a potential predictor marker for recurrence. Univariate and multivariate analysis were carried out to evaluate adjusted and unadjusted odds ratios (Ors) with 95% confidence intervals (CI) as a measure of the relative risk of relapse associated with the risk factors under investigation. Our data showed that the median value of ADAMTS13 activity and antigen levels at remission were significantly lower in patients with recurrent TTP than in patients with no relapse (ADAMTS13 activity: 12% vs. 41%; p=0.007; ADAMTS13 antigen: 36% vs 58%; p=0.003). Furthermore, the prevalence of patients with severe ADAMTS13 deficiency (≤10%) was significantly higher in the group of patients who relapsed (OR=2.9 CI95% 1.3–6.8, p=0.01). The prevalence of anti-ADAMTS13 autoantibodies (with or without neutralizing activity) resulted to be significantly higher in patients with recurrent TTP (OR= 3.1 CI 95% 1.4–7.3, p=0.006). A higher VWF antigen levels or the presence of ultralarge VWF (ULVWF) multimers at remission did not increase the risk of recurrence (p=0.4 for VWF:Ag and p=0.7 for ULVWF multimers). In conclusion, our data showed that the association of severe ADAMTS13 deficiency and the presence of anti-ADAMTS13 autoantibodies is a negative prognostic marker at remission and increases the relative risk of TTP recurrence by 3.6 times (OR=3.6 CI95% 1.4–9). Therefore our results would suggest that our efforts should go in the direction of maintenance therapy which aims at reducing or abolishing the presence of antibodies during remission and increasing the level of ADAMTS13 in plasma in order to prevent the recurrence of TTP.

Clinical Characteristics of Thrombotic Thrombocytopenic Purpura with Severe ADAMTS13 Deficiency

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4666-4666
Author(s):  
Moon Jang ◽  
So Young Chong ◽  
Inho Kim ◽  
Chul W. Jung ◽  
Doyeun Oh
Keyword(s):  
Mortality Rate ◽  
Serum Creatinine ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Clinical Significance ◽  
Sodium Dodecyl ◽  
Prognostic Significance ◽  
Adamts13 Activity ◽  
Lower Serum ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Abstract 4666 The clinical significance of ADAMTS13 activity for response to treatment, mortality rate, recurrence, and prognosis is unclear. Therefore, we investigated the characteristics of severe ADAMTS13 deficiency and evaluated its clinical significance in Thrombotic thrombocytopenic purpura (TTP). The Korean TTP Registry includes 66 patients from 13 teaching hospitals in Korea who received the diagnosis of TTP from January 2005 to December 2008. Blood samples obtained upon admission were sent for ADAMTS13 analysis (multimer analysis by sodium dodecyl sulfate electrophoresis and/or ELISA) to a central laboratory along with patient clinical information. After 6 months, patient data regarding treatment, response, and prognosis were collected on standardized report forms. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels (P=0.001) and WBC counts (P=0.050) than patients with non-severe ADAMTS13 deficiency. Although severe ADAMTS13 deficiency was associated with better response rate (75% vs 53%, P=0.145), remission rate (81% vs 61%, P=0.209), and mortality rate (19% vs 31%, P=0.508) than non-severe ADAMTS13 deficiency, treatment outcomes did not differ significantly between groups. After adjusting for clinical and laboratory features, multivariate analysis did not reveal any independent risk factors for TTP-associated mortality. Patients with severe ADAMTS13 deficient had lower serum creatinine levels and WBC counts at presentation but Severe ADAMTS13 activity deficiency at TTP diagnosis does not appear to have prognostic significance. Disclosures: No relevant conflicts of interest to declare.

FRETS-VWF73 rather than CBA assay reflects ADAMTS13 proteolytic activity in acquired thrombotic thrombocytopenic purpura patients

2014 ◽  
Vol 112 (08) ◽  
pp. 297-303 ◽  
Author(s):  
Ilaria Mancini ◽  
Carla Valsecchi ◽  
Luca Lotta ◽  
Louis Deforche ◽  
Silvia Pontiggia ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Proteolytic Activity ◽  
Binding Activity ◽  
Adamts13 Activity ◽  
Flow Conditions ◽  
Thrombocytopenic Purpura ◽  
Severe Deficiency ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryCollagen-binding activity (CBA) and FRETS-VWF73 assays are widely adopted methods for the measurement of the plasmatic activity of ADAMTS13, the von Willebrand factor (VWF) cleaving-protease. Accurately assessing the severe deficiency of ADAMTS13 is important in the management of thrombotic thrombocytopenic purpura (TTP). However, non-concordant results between the two assays have been reported in a small but relevant percentage of TTP cases. We investigated whether CBA or FRETS-VWF73 assay reflects ADAMTS13 proteolytic activity in acquired TTP patients with non-concordant measurements. Twenty plasma samples with non-concordant ADAMTS13 activity results, <10% using FRETS-VWF73 and ≥20% using CBA, and 11 samples with concordant results, <10% using either FRETS-VWF73 and CBA assays, were analysed. FRETS-VWF73 was performed in the presence of 1.5 M urea. ADAMTS13 activities were also measured under flow conditions and the VWF multimer pattern was defined in order to verify the presence of ultra-large VWF due to ADAMTS13 deficiency. In FRETS-VWF73 assay with 1.5 M urea, ADAMTS13 activity significantly increased in roughly 50% of the samples with non-concordant results, whereas it remained undetectable in all samples with concordant measurements. Under flow conditions, all tested samples showed reduced ADAMTS13 activity. Finally, samples with non-concordant results showed a ratio of high molecular weight VWF multimers higher than normal. Our results support the use of FRETS-VWF73 over CBA assay for the assessment of ADAMTS13 severe deficiency and indicate urea as one cause of the observed differences.

von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 778-785 ◽  
Author(s):  
Giuseppe Remuzzi ◽  
Miriam Galbusera ◽  
Marina Noris ◽  
Maria Teresa Canciani ◽  
Erica Daina ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Acute Phase ◽  
Von Willebrand Factor ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Uremic Syndrome ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Whether measurement of ADAMTS13 activity may enable physicians to distinguish thrombotic thrombocytopenic purpura (TTP) from hemolytic uremic syndrome (HUS) is still a controversial issue. Our aim was to clarify whether patients with normal or deficient ADAMTS13 activity could be distinguished in terms of disease manifestations and multimeric patterns of plasma von Willebrand factor (VWF). ADAMTS13 activity, VWF antigen, and multimeric pattern were evaluated in patients with recurrent and familial TTP (n = 20) and HUS (n = 29). Results of the collagen-binding assay of ADAMTS13 activity were confirmed in selected samples by testing the capacity of plasma to cleave recombinant VWF A1-A2-A3. Most patients with TTP had complete or partial deficiency of ADAMTS13 activity during the acute phase, and in some the defect persisted at remission. However, complete ADAMTS13 deficiency was also found in 5 of 9 patients with HUS during the acute phase and in 5 patients during remission. HUS patients with ADAMTS13 deficiency could not be distinguished clinically from those with normal ADAMTS13. In a subgroup of patients with TTP or HUS, the ADAMTS13 defect was inherited, as documented by half-normal levels of ADAMTS13 in their asymptomatic parents, consistent with the heterozygous carrier state. In patients with TTP and HUS there was indirect evidence of increased VWF fragmentation, and this occurred also in patients with ADAMTS13 deficiency. In conclusion, deficient ADAMTS13 activity does not distinguish TTP from HUS, at least in the recurrent and familial forms, and it is not the only determinant of VWF abnormalities in these conditions.

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