Thrombocytopenia-associated multiple organ failure (TAMOF) is a poorly understood syndrome in critically ill children. ADAMTS-13, formerly known as von Willebrand factor (VWF) cleaving protease, is decreased in adults with VWF mediated thrombotic microangiopathy, and intensive plasma exchange (PEx) both replenishes ADAMTS-13 and improves outcome in these patients. We hypothesized that children with TAMOF syndrome have decreased ADAMTS-13 activity which can be replenished with PEx. In the first of two consecutive studies, relationships between platelet count, VWF multimers, ADAMTS-13 activity, plasminogen activator inhibitor-1 (PAI-1) and prothrombin time (PT) were analyzed in children with and without TAMOF. In the second study, children with severe TAMOF (platelet counts<100,000/mm3 and ≥3 organ failure) were randomized to PEx or standard therapy. In the first study, children with TAMOF (n=28) had decreased ADAMTS-13 activity, but similar PAI-1 activity and PT compared to children with MOF without thrombocytopenia (n=9) (p<0.05). All non-survivors (n=7) had TAMOF, reduced ADAMTS 13 activity, and VWF-rich microvascular thromboses at autopsy. In the second study, PEx (n=5, median 12 days, 4–28 days) restored ADAMTS-13 activity and organ function, compared to standard therapy (n=5) (p<0.05). Children with TAMOF syndrome can have VWF mediated thrombotic microangiopathy. Similar to adult experience, PEx can replenish ADAMTS-13 activity and reverse organ failure in these children.

Menorrhagia is a common health problem in women, particularly those with bleeding disorders. Little is known about the course of menorrhagia or other bleeding symptoms in women with the most common congenital bleeding disorder, von Willebrand disease (vWD). We determined the prevalence of menorrhagia, bleeding symptoms and coagulation abnormalities associated with vWD, including factor VIII activity, von Willebrand factor (vWF) antigen, ristocetin cofactor and bleeding time (BT), on a cohort of 38 females with type 1 vWD referred for diagnosis and medical care. Menorrhagia was the most common bleeding symptom in females with vWD, occurring in 93.1% of adult women. Menorrhagia was also the most common initial bleeding symptom, occurring in 53.1% of adult women in all of whom it began at menarche, median 14 years of age. There was a delay from initial bleeding symptoms, at median age 12 years, to diagnosis, at median age 16 years, P=0.0049. Although 94% undergoing surgery had previous bleeding, a vWD diagnosis was known preoperatively in only 6.2%, resulting in potentially preventable bleeding. In summary, menorrhagia is the most common bleeding symptom in females with vWD and begins at menarche. Obtaining a personal and family bleeding history promotes early diagnosis, potentially prevents postoperative bleeding, and improves the health of women with vWD.

Platelets are activated in sickle cell disease (SCD), and particularly during vaso-occlusive episodes (VOE). Thrombospondin-1 (TSP1), a major secretory product of activated platelets, is increased in the circulation in VOE and binds to sickle red blood cells (RBC) promoting vascular adhesion. Thus, we hypothesized that TSP1 may represent a plasma biomarker of disease severity in SCD. We tested the plasma collected from patients in steady state (n = 27) and VOE (n = 14), as well as healthy controls (n = 17) at the University of Pittsburgh Medical Center (UPMC), and from patients in steady state enrolled in the walk-PHaSST clinical trial (n = 483). We found that TSP1 levels were increased in VOE in the UPMC cohort. Among steady-state patients at UPMC, TSP1 values correlated positively with lifetime history of acute chest syndrome (r = 0.72, P < 0.0001) and hemoglobin concentration (r = 0.49, P = 0.01), and negatively with markers of hemolysis, such as LDH (r = −0.50, P = 0.009). Analysis of the walk-PHaSST cohort also showed a positive association between TSP1 levels and hydroxyurea use (r = 0.14, P = 0.003), and confirmed the negative associations with the severity of hemolysis. Our results suggest that TSP1 levels are associated with more VOE, hydroxyurea use and lower rates of hemolysis. High TSP1 concentrations may indicate higher risk of the viscosity/vaso-occlusion phenotype of SCD.

Background If ‘bridging’ to allotransplantation is to be achieved by a pig liver xenograft, adequate hepatic function needs to be assured. Methods We have studied hepatic function in baboons after transplantation of livers from α1,3-galactosyltransferase gene-knockout (GTKO,n=1) or GTKO pigs transgenic for CD46 (GTKO/CD46,n=5). Monitoring was by liver function tests and coagulation parameters. Pig-specific proteins in the baboon serum/plasma were identified by Western blot. In 4 baboons, coagulation factors were measured. The results were compared with values from healthy humans, baboons, and pigs. Results Recipient baboons died or were euthanized after 4-7 days following internal bleeding associated with profound thrombocytopenia. However, parameters of liver function, including coagulation, remained in the near-normal range, except for some cholestasis. Western blot demonstrated that pig proteins (albumin, fibrinogen, haptoglobin, plasminogen) were produced by the liver from day 1. Production of several pig coagulation factors was confirmed. Conclusions After the transplantation of genetically-engineered pig livers into baboons (1) many parameters of hepatic function, including coagulation, were normal or near-normal; (2) there was evidence for production of pig proteins, including coagulation factors, and (3) these appeared to function adequately in baboons, though inter-species compatibility of such proteins remains to be confirmed.

The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide yield high response rates in patients with multiple myeloma, but the use of IMiDs in multiple myeloma is associated with neutropenia and increased risk for venous thromboembolism (VTE) by mechanisms that are unknown. We show that IMiDs downregulate PU.1, a key transcription factor involved in granulocyte differentiation in vitro and in patients treated with lenalidomide. Loss of PU.1 results in transient maturation arrest with medullary accumulation of immature myeloid precursors and subsequent neutropenia. Accumulation of promyelocytes leads to high levels of the platelet aggregation agonist, cathepsin G stored in the azurophilic granules of promyelocytes. High levels of cathepsin G subsequently may increase the risk of VTE. To our knowledge, this is the first report investigating the underlying mechanism of IMiD-induced neutropenia and increased risk of VTE in multiple myeloma. (Blood. 2010;115:605-614) IntroductionThalidomide and its immunomodulatory derivatives (IMiDs), such as lenalidomide (CC-5013) and pomalidomide (CC-4047), represent a novel class of agents with potent activity against multiple myeloma (MM). However, the use of IMiDs has been associated with 2 major adverse effects: (1) higher incidence of neutropenia that is the most common reason for holding or termination of treatment, and (2) increased risk for venous thromboembolism (VTE) that is further amplified with combination therapy.In 2 multicenter randomized trials including 353 patients with MM, 23% of patients experienced grade 3 or 4 neutropenia. 1,2 In patients receiving pomalidomide, the rate of grade 3 or 4 neutropenia was 32% in a phase 2 trial 3 and 58% in a phase 1 trial. 4 Clinical trials on myelodysplastic syndrome have shown that the frequency of lenalidomide-induced neutropenia is dose dependent and increases with duration of treatment. 5,6 The mechanism of induction of neutropenia is unclear, especially because IMiDs are not stem cell toxic and in vitro induce the expansion of CD34 ϩ cells. 7 Previous studies have shown that thalidomide/IMiDs increase the risk of VTE in patients with MM, especially if used in combination with dexamethasone. In 2 phase 3 trials comparing lenalidomide plus dexamethasone versus dexamethasone alone, the incidence of VTE in the absence of thromboembolic prophylaxis was 4 times greater in the lenalidomide/dexamethasone group, 16% versus 4%. 1,2,8 In a phase 1 trial evaluating pomalidomide alone, in 24 patients with refractory and/or relapsed MM, 4 (17%) developed VTE without thromboembolic prophylaxis during the first year of therapy. 4 The observation that aspirin is effective in preventing IMiD-induced VTE, 9 however, sharply contrasts with the lack of efficacy of aspirin in VTE prevention, suggesting that the pathogenesis in IMiD-induced VTE is different from that of "standard" VTE and, moreover, that platelet activation might contribute to thalidomide/IMiD-induced VTE.In this study, we analyzed the effect of IMiDs on granulocytic pr...

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The factor V mutation is a common cause of venous thromboses but may also be associated with the early presentation of arterial thrombotic events. The APC resistance test is a sensitive screening assay but has limitations of its specificity in clinical practice.

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