Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates?

Hemophilia A (HA) and B are inherited bleeding disorders caused by a deficiency of factor VIII or factor IX, respectively. The current standard of care is the administration of recombinant or purified factor. However, this treatment strategy still results in a high economic and personal burden to patients, which is further exacerbated by the development of inhibitors—alloantibodies to factor. The treatment landscape is changing, with nonfactor therapeutics playing an increasing role in what we consider to be the standard of care. Emicizumab, a bispecific antibody that mimics the function of factor VIIIa, is the first such nonfactor therapy to gain US Food and Drug Administration approval and is rapidly changing the paradigm for HA treatment. Other therapies on the horizon seek to target anticoagulant proteins in the coagulation cascade, thus “rebalancing” a hemorrhagic tendency by introducing a thrombotic tendency. This intricate hemostatic balancing act promises great things for patients in need of more treatment options, but are these other therapies going to replace factor therapy? In light of the many challenges facing these therapies, should they be viewed as a replacement of our current standard of care? This review discusses the background, rationale, and potential of nonfactor therapies as well as the anticipated pitfalls and limitations. This is done in the context of a review of our current understanding of the many aspects of the coagulation system.

Mechanisms and Therapeutic Modulation of the Bleeding Tendency in Genetically-Engineered Von Willebrand Disease Type 2B Mice

Von Willebrand disease type 2B (VWD2B) is characterized by an abnormal increased affinity of von Willebrand factor (VWF) for platelets and related to mutations in the A1 domain of VWF. In patients, the VWD2B-mutant p.V1316M is specifically associated with a severe phenotype including hemorrhagic tendency, loss of high molecular weight VWF multimers, thrombocytopenia and platelet dysfunction related to defective αIIbβ3 integrin activation (Casari et al. JCI 2013, 123:5071). Genetically-engineered mice carrying the p.V1316M mutation (V1316M+/+ mice) perfectly mimic the human phenotype. We used this murine model to investigate the relative contribution of platelet count and platelet dysfunction to the occurrence of bleeding tendency and explore new therapeutic options. Bleeding tendency was evaluated using a novel tail-vein transection bleeding model involving the specific transection of the lateral vein at standardized depth and diameter (0.7 and 2.3mm respectively). Time (TVT) and blood loss were measured in wild-type (WT) and V1316M+/+ mice at baseline and after platelet count alteration. Compared to WT mice (platelet count: 1019±154G/L, n=58), V1316M+/+ mice (platelet count: 455±139G/L, n=52) have a significant increase (p<0.01) in TVT (25±9min, n=12 vs 2±1min, n=14) and blood loss (448±273µl vs 34±19µl). Induced thrombocytopenia (after infusion of anti-GPIb antibody) in WT mice (platelet count: 347±93G/L, n=6), to a similar level of V1316M+/+ mice, did not induce a hemorrhagic tendency (TVT: 2±1min, blood loss: 14±13µl). An increased bleeding phenotype in WT mice was exclusively observed in case of severe thrombocytopenia (platelet count: 70±25G/L, TVT>30min, blood loss: 532±168ml, n=6). Conversely, romiplostim-treated V1316M+/+ mice with normalized platelet count (platelet count: 866±100G/L, n=8) did not improve their bleeding tendency (TVT: 21±8min, blood loss: 448±282ml). These results suggest the bleeding phenotype in V1316M+/+ mice is independent of their thrombocytopenia, and could be related to the p.V1316M-associated defect in platelet function in general, and αIIbβ3 integrin activation in particular. Based on the hemostatic efficacy of recombinant activated factor VII (rFVIIa) in Glanzmann thrombasthenia, we tested rFVIIa in thrombocytopenic V1316M+/+ mice. A single infusion of rFVIIa (3 mg/kg) induced a complete and immediate correction of the bleeding phenotype (TVT: 4±2min, blood loss: 69±25ml, n=6). Thrombin generation measured in platelet-rich plasma before and after treatment showed a significant reduction of the lag time (1.13min, n=12 vs 1.8min, n=8 respectively, p<0.01). In conclusion, genetically-engineered mice carrying the VWD2B p.V1316M mutation display a bleeding phenotype that is not explained by their reduced platelet count, but is possibly related to the impaired platelet function induced by this VWF mutant. The bleeding tendency was rapidly and completely controlled by using rFVIIa. Based on these promising data, it would be of interest to consider rFVIIa as a therapeutic option in VWD-2B patients characterized by a severe hemorrhagic phenotype. Disclosures No relevant conflicts of interest to declare.

DENGUE FEVER;

Background: Dengue fever & its complications have become a nightmare forcommon people in Asian countries including Pakistan. Besides environmental factorsresponsible for its transmission, there are many host factors too involved in its rapid spread.Objective: To assess risk factors for dengue fever among patients reporting at Liaquat UniversityHospital (LUH) Hyderabad. Study Design, Setting & Study duration: Descriptive crosssectional study was conducted at LUH, Hyderabad for six months i.e. from 15th May 2013 to 15thNovember 2013. Methods: 481 patients were registered through convenient sampling afterinformed verbal consent. Patients’ demographic features, clinical presentations & laboratoryreports were collected on a preformed proforma. Results: The reporting rate for dengue feverwas 18.5% & the mean age of presentation was 28.5 ± 3.5 years. Males were in majority (72.55%)3 & the average days of admission were 4.5 days; low platelets count (< 50,000/mm ) wasrecorded in 72% of cases; however 11.64% patients presented with hemorrhagic tendency. Agewas strongly associated with thrombocytopenia (p=0.04) & with occurrence of hemorrhage(p=0.03) in both genders; this association was more evident among males (p=0.01). Howeveramong uncomplicated cases no association was evident between gender & length of stay in(p=0.35). Conclusions: The alarmingly higher reporting rate of dengue fever necessitatescontextual preventive interventions. As younger age & male gender are the major risk factors forthis disease; therefore age-specific & gender-specific preventive strategies against this diseaseare recommended.

Tubeless Percutaneous Nephrolithotomy: Can be a Choice, Why Not?

Percutaneous nephrolithotomy (PCNL) has been widely accepted and is commonly used to treat renal calculi. The optimal drainage of kidney after PCNL has not been clearly determined yet. Placement of an 18F to 24F nephrostomy tube at the end of the procedure is accepted as standard of care to date. The main advantages are adequate renal drainage, hemostatic tamponade and providing renal access for second look PCNL. However, based on the concept that the purpose of the tube is only to maintain adequate drainage of the kidney, a “tubeless” approach has been developed by placing a ureteral stent or catheter to provide drainage after PCNL instead of a nephrostomy tube. Tubeless PCNL is an effective and safe procedure for treatment of renal stones in selected cases. This procedure can even be chosen for patients with previous renal surgery, and hemorrhagic tendency. By using this method, less postoperative pain and a shorter hospital stay can be achieved, when compared with conventional PCNL. There is a controversy over ideal drainage system after PCNL in recent years. Herein, we made a systematic review for efficacy and safety of tubeless PCNL, totally tubeless PCNL, discussed different variations and compared the outcomes of this technique with standart PCNL.

Clinical Analysis of 159 Times Acute Transfusion Reaction in Single Center.

Abstract 4196 Objective Retrospective analysis of acute transfusion reactions occurred in our hospital in recent years. Methods Investigate all hospitalized patients who transfused various blood components from November 2006 to July 2009. Results During study period, there were 27,672 times transfusion with 80,112 units various blood components, mainly red blood cells(RBCs), frozen plasma(FP) and leukocyte-depleted platelets(PLTs). Acute transfusion reactions occured in 143 patients of 159 times transfusion, including febrile nonhemolytic transfusion reactions(FNHTR), allergic transfusion reactions(ATR), transfusion-related acute lung injury(TRALI), transfusion-associated circulatory overload(TACO) and hemorrhagic tendency. The 143 enrolled patients, 87male and 56female, were between the age of 16 and 94. The incidence rate of acute transfusion reaction was 0.57%, FNHTR and ATR accounted for 96.23%. Of all blood components, the incidence rates of acute reaction were 0.35%, 0.50% and 1.82% respectively in RBCs, FP and PLTs transfusions. In 159 times of acute transfusion reactions, the constituent ratios of 0∼3 times and more than 3 times transfusion were 23.27%, 18.87%, 7.55%, 4.40% and 45.91%, respectively. Conclusion Most of acute transfusion reactions were FNHTR and ATR. The highest incidence rate was in platelets transfusion, and the most constituent ratio was in patients who have received more than 3 times transfusion. Disclosures: No relevant conflicts of interest to declare.