The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors.

Endogenous c-MYC (MYC) has been reported to be a potential pharmacological target to trigger ubiquitous tumor regression of pancreatic neuroendocrine tumors (PanNETs) and lung tumors. Recently inhibitors of bromodomain and extra-terminal (BET) family proteins have shown antitumor effects through the suppression of MYC in leukemia and lymphoma. In this paper, we investigated the antitumor activity of a BET protein bromodomain inhibitor (BETi) CPI203 as a single agent and in combination with rapamycin in human PanNETs. We found that exposure of human PanNET cell lines to CPI203 led to downregulation of MYC expression, G1 cell cycle arrest and nearly complete inhibition of cell proliferation. In addition, overexpression of MYC suppressed the growth inhibition caused by CPI203 and knockdown of MYC phenocopied the effects of CPI203 treatment. These findings indicate that suppression of MYC contributed to the antiproliferative effects of BETi inhibition in human PanNET cells. Importantly, CPI203 treatment enhanced the antitumor effects of rapamycin in PanNET cells grown in monolayer and in three-dimensional cell cultures, as well as in a human PanNET xenograft model in vivo. Furthermore, the combination treatment attenuated rapamycin-induced AKT activation, a major limitation of rapamycin therapy. Collectively, our data suggest that targeting MYC with a BETi may increase the therapeutic benefits of rapalogs in human PanNET patients. This provides a novel clinical strategy for PanNETs, and possibly for other tumors as well.

Immunologic recovery after autologous blood stem cell transplantation in patients with AL-amyloidosis.

We prospectively studied absolute lymphocyte (ALC) and monocyte counts (AMC), lymphocyte subsets and proliferative in vitro responses to mitogen and antigen in 12 patients with AL-amyloidosis (AL) undergoing autologous blood stem cell transplantation (SCT) with high-dose i.v. melphalan. Myeloid and lymphoid recovery (>500 per microl) occurred in a median of 10 days post SCT. While there was a continuous decline in the number of CD4+ T cells at 3 months, ALC, AMC, B cells (CD19+), CD8+ T cells, and NK cells (CD16+/56+) returned to baseline. While T cell proliferative responses to phytohemagglutinin (PHA) remained depressed, B cell function measured by the proliferative response to staphylococcal antigen returned to baseline by 3 months. To supplement our findings, we retrospectively evaluated ALC, AMC and serum immunoglobulin levels in a separate group of patients treated with the same protocol at our institution. ALC and AMC recovery was similar to the pattern observed in the initial study group. Immunoglobulin levels remained within normal ranges at 3 and 12 months after SCT. Of 50 patients who were followed for a minimum of 1 year following SCT, seven (14%) developed shingles and one (2%) had PCP pneumonia. In conclusion, cellular immune function, reflected by absolute numbers of CD4+ T cells and PHA responsive T cell proliferation, is significantly suppressed at 3 months after SCT in patients with AL, and this post-transplant immunosuppression is associated with a low but clinically meaningful occurrence of opportunistic infections typical of T cell immunosuppression.

Efficacy of a sucrose-formulated recombinant factor VIII used for 22 surgical procedures in patients with severe haemophilia A.

A sucrose-formulated recombinant FVIII (rFVIII-SF) was investigated under clinical trial conditions during surgical procedures in previously treated patients (PTPs). Fifteen PTPs with severe haemophilia A (FVIII < or = 1%) underwent 22 surgical procedures. The procedures performed cover a spectrum from minor to major surgery. Haemostatic outcome was assessed by the investigators to be excellent in 16 procedures and good in the remaining six procedures. It is concluded that rFVIII-SF is efficacious and safe in severe haemophilia A patients undergoing minor or major surgery.

Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy--International Kogenate-FS Study Group.

To add an increased level of safety to antihemophilic factor replacement therapy, a full-length, recombinant Factor VIII (rFVIII) product has been developed without human-derived plasma proteins during purification and formulation and using an additional solvent/detergent viral inactivation step. This first clinical trial of a sucrose-formulated full-length rFVIII (rFVIII-FS) was conducted in previously treated patients (> or = 100 prior exposure days) with severe (<2% FVIII) hemophilia A in North America (NA) and Europe (EU). Pharmacokinetic profiles for rFVIII-FS were compared with those of currently licensed rFVIII product (Kogenate) in 35 patients. Safety and efficacy during home therapy were evaluated in 71 patients. The new formulation displayed a pharmacokinetic profile similar to that of rFVIII. Patients on home therapy received a cumulative total of 11,867 exposure days, 12,546 infusions, and 22,443,694 IU of rFVIII-FS. Of 2585 bleeds, 93.5% were treated with 1-2 infusions and 80.5% of responses were rated as excellent or good. No evidence of de novo inhibitor formation was observed. Only 0.27% of infusions were associated with any drug-related adverse event. Except for an episode of intermittent chest pain with palpitations which ceased after treatment with analgesics, associated adverse events were mild or moderate. Overall, rFVIII-FS provided excellent hemostatic control, was well-tolerated, and caused no significant adverse effects, thus demonstrating safety and efficacy for treatment of bleeds in patients with hemophilia A.

Safety and efficacy of solvent/detergent-treated antihaemophilic factor with an added 80 degrees C terminal dry heat treatment in patients with haemophilia A.

Plasma-derived factor VIII concentrates remain an important resource for haemophilia A patients. To improve the safety of these preparations, various methods of viral removal and inactivation have been used that are designed to eliminate both enveloped and non-enveloped viruses. There have been rare reports that some viral inactivation processes altered the immunogenicity of some concentrates, leading to the development of factor VIII inhibitors in previously treated haemophilia A patients. This study evaluated the safety, efficacy and lack of neo-antigenicity of a highly purified factor VIII preparation which undergoes both solvent/detergent treatment and final dry heat treatment at 80 degrees C for 72 h. The study included: (i) a single blind, single-dose crossover pharmacokinetic study in 18 previously treated patients, comparing sibling lots of the unheated preparation (Koate(R)-HP) and the heat-treated preparation (Koate(R)-DVI), and (ii) an extended home treatment programme for 36 patients at two haemophilia treatment centres primarily to assess immunogenicity. Clinical parameters were assessed at regular intervals. The results confirm that Koate(R)-HP and Koate(R)-DVI are bioequivalent, and that Koate(R)-DVI is safe and efficacious for treatment of acute bleeding episodes and for surgery. Furthermore, the heat-treated preparation is not associated with the development of inhibitors in previously treated patients.

Intermediate-dose intravenous melphalan and blood stem cells mobilized with sequential GM+G-CSF or G-CSF alone to treat AL (amyloid light chain) amyloidosis.

AL amyloidosis patients ineligible for dose-intensive melphalan (200 mg/m2) were enrolled on a phase 11 trial to be treated with two cycles of intermediate-dose melphalan (IDM 100 mg/m2) and mobilized blood stem cells (BSC). For mobilization patients were randomized to either GM-CSF 250 microg/m2 for 3 d followed by G-CSF 10 microg/ kg for 3 d (GM+G), or G-CSF 10 microg/kg for 6 d (G-alone), with leukaphereses on days 5, 6 and 7. To minimize morbidity, we planned to support each cycle with 3 5 x 106 CD34+ cells/kg and had a collection target of 7 x 10(6) CD34+ cells/kg. Those who did not achieve the target were treated with one cycle of IDM. 30 patients, a median of 62 years old and 7 months from diagnosis, were enrolled. Both mobilization regimens were generally well tolerated, and similar in terms of CD34+ cells and CFU-GM collected, but only 6/28 patients achieved the collection target (GM+G four, G-alone two). Despite a 19% incidence of grade 4 toxicities, IDM therapy was well tolerated. At a median follow-up of 24 months (19-36) 57% of patients had survived, 17% with durable complete haematological responses and 40% with improved or stable amyloid organ involvement, including 3/9 patients with predominant cardiac amyloid who are alive 2-3 years after treatment. The 100 d mortality was 20%. In conclusion, no definitive differences were identified between the mobilization regimens and IDM was an active regimen in AL for selected patients.

Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients.

AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < . 01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

Phase I trial of the colloidal dispersion formulation of 9-amino-20(S)-camptothecin administered as a 72-hour continuous intravenous infusion.

The camptothecins are a class of potent cytotoxic anticancer agents that interact with the nuclear enzyme topoisomerase I to produce lethal DNA strand cleavages. 9-Amino-20(S)-camptothecin (9AC) was introduced into Phase I clinical trials in dimethylacetamide and polyethylene glycol 400 in a 10 mM phosphoric acid vehicle for i.v. solubility. A lyophilized colloidal dispersion (CD) of 9AC for reconstitution with 20% dextrose in normal saline was developed as an alternative formulation. Patients (ages 25-75 years) with normal liver and kidney function, Eastern Cooperative Oncology Group performance status < or = 2, and up to two prior chemotherapy regimens were treated. The initial infusion rate was 37.5 micrograms/m2/h as a 72-h continuous infusion (2.7 mg/m2 total dose). Patient cohorts were treated with escalating infusion rates until grade 4 hematological or other grade 3 toxicity developed. Pharmacokinetic sampling was performed on all patients, and 9AC lactone concentrations in plasma were determined by a high-performance liquid chromatographic assay. Twenty-five patients received a total of 65 courses of 9AC CD at doses from 2.70 to 4.65 mg/m2. The dose-limiting toxicity was neutropenia, with little nonhematological toxicity. Nonlinear regression analysis of pooled patient data yielded a total plasma clearance of 30.3 +/- 4.5 liters/h/m2, a half-life of 22.5 +/- 8.5 h, a mean residence time of 9.7 +/- 3.5 h, and a steady-state volume of distribution of 325 +/- 145 liters/m2. Although no objective responses were seen, 9 of 25 patients exhibited stable disease for 2-6 months. The plasma pharmacokinetics of 9AC lactone in cancer patients were comparable between the 9AC CD and soluble formulations. The dosing regimen recommended for Phase II trials of the 9AC CD formulation is 54.2 micrograms/m2/h, given as a 72-h continuous i.v. infusion every 3 weeks.

Tiazofurin effects on IMP-dehydrogenase activity and expression in the leukemia cells of patients with CML blast crisis.

Tricot et al have reported that the nucleoside analog tiazofurin can induce hematologic remissions in patients with chronic myelogenous leukemia in blast crisis (CML-BC). These reports prompted us to begin a derivative, phase II trial of tiazofurin in CML-BC to determine if the promising findings reported by these investigators could be reproduced. In our ongoing trial patients receive tiazofurin by IV infusion (2200-4400 mg/m2 over 1 hr) once every 24-48 hrs for up to 10 days. Each of 3 patients, treated to date on this trial, experienced substantial hematologic responses with normalization of WBC counts and complete or partial clearance of blasts from the blood within 4-11 days of treatment. These responses were relatively brief, in that leukemic blasts reaccumulated in the marrow and blood of patients within 4 weeks following treatment, but were re-induced with subsequent courses of treatment. Of interest, the rates of blast cell reaccumulation appeared to increase progressively following sequential courses of treatment. Tiazofurin, which inhibits IMP-dehydrogenase (IMPDH) and blocks guanine ribonucleotide synthesis, has been shown to increase IMPDH mRNA expression in various cell lines in vitro, as an apparently compensatory response to guanylate deprivation. Studies of IMPDH mRNA expression in the leukemic blasts of CML-BC patients receiving tiazofurin treatment showed that this same phenomenon occurs in vivo. Since IMPDH activity is linked to the proliferative activity of neoplastic cells an amplification of IMPDH message expression induced by tiazofurin may lead to an increased sensitivity of the leukemic clone to cycle active agents.

Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients.

The morbidity and lethality of AL amyloidosis is caused by the deposition of lg light chains as fibrillar amyloid protein in vital organs, disrupting their function, and not by the generally low burden of clonal plasma cells that produce the paraproteins. Survival of patients with AL amyloidosis is no more than 1 to 2 years from the time of diagnosis with current management approaches. Clearly, more effective therapies are needed for this rapidly lethal disease. Five patients were treated with dose-intensive melphalan and blood stem cell support and followed for a period of 1 year. Patients were diagnosed with AL amyloidosis by tissue biopsy and categorized by performance status and organ involvement. Their plasma cell dyscrasias were evaluated with immunofixation electrophoresis of serum and urine specimens, quantitative serum lgs, and immunohistochemical staining of bone marrow biopsy specimens. After treatment with dose-intensive intravenous melphalan followed by infusion of autologous growth-factor-mobilized blood stem cells, clinical evaluations and plasma cell studies were repeated at 3 and 12 months. Three men and 2 women aged 38 to 53 years were treated. Median performance status (SWOG) was 2 (1 to 3), and clinical presentations included nephrotic syndrome (n = 1), symptomatic cardiomyopathy (n = 1), gastrointestinal involvement with polyneuropathy (n = 2), and hepatomegaly (n = 1). With a median follow-up of 13 months (12 to 17 months), all five patients are well and have shown stable or improved performance status and clinical remission of organ-related dysfunction, including a 50% reduction in daily proteinuria with no change in creatinine, reversal of symptoms of cardiomyopathy and reductions of posterior wall and septal thickening, reversal of polyneuropathy and gastric atony, and resolution of hepatomegaly by computed tomographic scan. In 3 of the 5 patients (60%) at 12 months after treatment, plasma cell dyscrasias could not be detected. Dose-intensive chemotherapy with intravenous melphalan and growth-factor-mobilized blood stem cell support is feasible therapy for patients with AL amyloidosis, even when there is clinical evidence of cardiac involvement. At least some patients with AL amyloidosis achieve complete remission of their plasma cell dyscrasia, improvement in performance status, and clinical remission of organ-specific disease after this form of treatment.

Collection of mobilized blood progenitor cells for hematopoietic rescue by large-volume leukapheresis.

BACKGROUND: Mobilized blood progenitor cells rapidly reconstitute hematopoiesis in patients after dose-intensive chemotherapy. However, optimal timing and methods of mobilized blood progenitor cell collection have yet to be fully defined. STUDY DESIGN AND METHODS: The utility of large-volume leukapheresis (LVL; > 15 L blood processed) in collecting target doses of mononuclear cells (7 x 10(8)/kg) for use in autologous hematopoietic rescue was investigated. LVL was begun at a standardized interval (14 days) after a course of limited chemotherapy and subsequent daily recombinant human granulocyte-macrophage-colony-stimulating factor administration to mobilize blood progenitor cells into the circulation. With each LVL procedure, mononuclear cells, colony-forming units-granulocyte-macrophage (CFU-GM), burst-forming units-erythroid, mixed colonies, total clonogenic progenitor cells, and CD34+ cells collected per kg of patient weight were counted. After high-dose chemotherapy and infusion of cryopreserved mobilized blood progenitor cells, the days needed for neutrophils to reach levels of > 0.5 x 10(9) per L and for platelets to reach levels of > 20 x 10(9) per L were recorded. RESULTS: In 14 previously treated cancer patients, an average of 28.9 +/- 4.9 L of blood was processed per LVL (n = 35) to collect medians of 2.5 x 10(8) mononuclear cells per kg (range, 1.0-7.4), 14 x 10(4) CFU-GM per kg (0-208), 27 x 10(4) clonogenic progenitor cells per kg (0-370), and 2.8 x 10(6) CD34+ cells per kg (0-112.5). Fifty-seven percent of patients (8/14) required one or two LVL procedures to collect adequate blood progenitor cells (range, 1-4). After dose-intensive chemotherapy, 13 patients received medians of 6.8 x 10(8) mononuclear cells per kg (range, 5.1-9.9), 53 x 10(4) CFU-GM per kg (9-208), and 12 x 10(6) CD34+ cells per kg (3.6-112.5). Rapid hematopoietic reconstitution occurred with 10 days (range, 8-12) and 9 days (6-15), respectively, for neutrophil and platelet recoveries. CONCLUSION: Scheduled LVL, beginning on Day 14 after the administration of granulocyte-macrophage-colony-stimulating factor following chemotherapy, is a convenient and efficient method of collecting blood progenitor cells. The mononuclear cells so obtained effected consistent and rapid hematopoietic reconstitution in a highly reproducible manner in a group of heavily treated patients.

Chronic tension pneumothorax mimicking tension bullae. Use of video-assisted thoracoscopy for diagnosis.

A 48-year-old patient had a lucent right hemithorax and marked mediastinal shift of unknown duration that appeared on a chest radiograph. He was unchanged symptomatically from his baseline status. Video-assisted thoracoscopy was used to distinguish between tension from a giant bulla and a chronic tension pneumothorax.

Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding.

A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is characterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(ogen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor XIII deficiency, alpha 2-antiplasmin deficiency, or dysfibrinogenemia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half normal antigen and normal activity of platelet PAI-1. The low concentration of plasma PAI-1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAI-1 deficiency. Studies on this patient emphasize a clear correlation between decreased plasma PAI-1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAI-1 in the balance between the coagulation and fibrinolytic mechanisms.

Excessive fibrinolysis in amyloidosis associated with elevated plasma single-chain urokinase.

Severe bleeding resulting from excessive fibrinolysis has been observed in patients with primary amyloidosis. The authors studied a patient with this hemostatic disorder before and during therapy with epsilon-aminocaproic acid. Excessive fibrinolysis was associated with depressed plasma concentrations of coagulation Factors XII, XI, high-molecular-weight kininogen, and Factors VIII and V; and plasminogen and alpha-2-plasmin inhibitor. These deficiencies were corrected with treatment. The functional and antigenic concentrations of tissue plasminogen activator and plasminogen activator inhibitor in the patient's plasma were normal. Urokinase-type activator activity and antigen were three to five times elevated in the patient's plasma. Results of immunoprecipitation showed that single-chain urokinase-type activator was the primary urokinase-type activator species in the patient's plasma. Excessive fibrinolysis in patients with amyloidosis results from increased plasma single-chain urokinase-type activator activity.

Pulmonary leukostasis secondary to all-trans retinoic acid in the treatment of acute promyelocytic leukemia in first relapse.

All-trans retinoic acid has recently been shown to induce differentiation of acute promyelocytic leukemia cells in vitro and in vivo. Clinical trials of patients treated de novo, in first relapse, and with resistant disease have achieved a high rate of complete remission (CR). The overall toxicity is substantially less than standard induction chemotherapy, with the notable exception of deaths attributed to the development of pulmonary leukostasis coinciding with a rapid increase in the number of mature neutrophils. This report describes a patient who developed pulmonary leukostasis in the absence of significant leukocytosis. The patient survived pulmonary leukostasis, resumed therapy, and achieved a CR. The case demonstrates features of leukostasis which are peculiar to the 'retinoic acid syndrome'.

Report of a variant t(1;15;17)(p36;q22;q21.1) in a patient with acute promyelocytic leukemia.

Chromosome analysis of bone marrow aspirate from a 46-year-old man with acute promyelocytic leukemia (APL) revealed a variant translocation, 46,XY,t(1:15;17)(p36;q22;q21.1). The breakpoints in chromosomes 15 and 17 appear to be the same as those in the more common translocation, t(15;17), associated with APL. The common translocation has been reported in up to 80% of cases of APL. Seventeen cases with variant translocations have been reported involving 15 alone, 17 alone, or 15, 17, and some other chromosome.

Isolation from commercial aurintricarboxylic acid of the most effective polymeric inhibitors of von Willebrand factor interaction with platelet glycoprotein Ib. Comparison with other polyanionic and polyaromatic polymers.

Solutions of commercial aurintricarboxylic acid (ATA) inhibit ristocetin- or shear stress-induced, von Willebrand factor (vWF)-mediated platelet aggregation by interacting with vWF and blocking its attachment to platelet membrane glycoprotein Ib. ATA has also been shown to prevent cyclic platelet clumping in a dog model of coronary artery thrombosis. Because these ATA solutions are actually a heterogeneous mixture of polyanionic, polycarboxylic polyaromatic polymers of molecular weight (Mr) 200 to greater than 6,000, we separated the most effective inhibitory components of commercial ATA using exclusion chromatography. ATA polymers larger than Mr 700 inhibited ristocetin-induced, vWF-mediated platelet aggregation more effectively than smaller ATA polymers, whereas shear-induced, vWF-mediated platelet aggregation was optimally inhibited by ATA polymers of Mr greater than or equal to 2,500. Platelet aggregation mediated by vWF was not inhibited by a nonphenolic, polyanionic polymer (polyglutamic acid) or by a polyphenolic ATA-like polymer (aurin) devoid of carboxyl groups. Polyanionic, polysulfonated aromatic polymers (polystyrene sulfonate) of Mr 35, 17.4, 8, and 4.6 x 10(3) inhibited ristocetin- and shear-induced, vWF-mediated aggregation with less potency on a mass/volume basis than large polymers of ATA. We conclude that a polyanionic, polycarboxylated, polyphenolic ATA polymer of Mr 2,500 is optimally potent as an inhibitor of shear- and ristocetin-induced, vWF-mediated platelet aggregation and is likely to be more effective than solutions of commercial ATA as an anti-arterial thrombotic agent.

Fetal and neonatal von Willebrand factor (vWF) is unusually large and similar to the vWF in patients with thrombotic thrombocytopenic purpura.

We have investigated the distribution of vWF multimers in blood from the umbilical cord of infants delivered vaginally and by caesarean section, from heel-stick blood collected 1 d post-partum, and from fetuses undergoing evaluation for Rh compatibility. To examine vWF multimers, plasma was separated by electrophoresis on SDS-agarose gels, overlaid with 125I-anti-vWF, and analysed by densitometry of autoradiographs. Neonatal and fetal plasma contained unusually large von Willebrand factor multimers (ULvWFM), not present in normal adult plasma, in shed blood from adults, in maternal plasma at the time of birth, or in plasma from adults deficient in vitamin K-dependent coagulation proteins. We conclude that ULvWFM, similar in size to vWF present in the Weibel Paladie bodies of endothelial cells, the alpha granules of platelets, and the plasma of patients with TTP, is present in the fetal circulation, at birth, and shortly after delivery.