PubMed Health⌕ Search

Biomedical subjects

Hau C Kwaan

Publications and source records attributed to Hau C Kwaan.

At least 19 recordsLinked to original sources
PubMed2005

Meeting report. Acute promyelocytic leukemia-associated coagulopathy, 21 January 2004, London, United Kingdom.

Despite successful treatment with all-trans retinoic acid and chemotherapy, life-threatening bleeding remains a challenging complication of acute promyelocytic leukemia (APL). Indeed, bleeding and thrombosis are major complications of APL that lead to early death in approximately 10% of patients despite the success of current treatment. This condition may be attributed, in part, to the diffuse activation of coagulation, hyperfibrinolysis, and non-specific proteolytic activity that is observed in patients with APL. Therapeutic agents that induce the differentiation of leukemia cells improve outcomes compared with those observed using chemotherapy alone. They also correct the hyperactivity of the coagulation and fibrinolytic systems, thereby reducing early death from bleeding. Prophylactic therapy with newer anticoagulants may prove beneficial in patients with APL, but this must be confirmed in well-designed, randomized, controlled trials. A workshop was convened 21 January 2004 in London, England, to discuss the clinical and biological aspects of the APL-associated coagulopathy and the application of recent findings to the management of patients with APL. Eight speakers participated in the workshop. This meeting report provides synopses of their presentations and a summary of highlights from the meeting.

Anticoagulants↗
PubMed2005

Thrombotic thrombocytopenic purpura: a diagnostic and therapeutic challenge.

With the discovery of the ultra-large von Willebrand factor (vWF) in the plasma of thrombotic thrombocytopenic purpura (TTP) patients and the pivotal role played by the ADAMTS13 metalloproteinase, many new challenges are facing both the researcher and the clinician for the diagnosis and treatment of this condition. As a result of these new discoveries, the range of disorders manifesting with many of the clinical features of the disease can now be reclassified into the idiopathic TTP, congenital TTP, and non-idiopathic TTP, based on the level of ADAMTS13 activity. The latter group includes drug-associated TTP. In this article, the background of the pathogenesis, and diagnostic and therapeutic approaches are reviewed. An emerging concept of the pathogenesis of TTP is presented. The merits of various diagnostic procedures including the assay of the ADAMTS13 activity and the immunoglobulin G inhibitory antibodies are discussed. Regarding the therapeutic aspect, although plasma exchange remains the mainstay, the question of addition of immunosuppressive agents comes up, especially in those patients who are refractory to plasma exchange and those that repeatedly relapse. A call for clinical trials to address the question of efficacy of various agents is made.

ADAM Proteins↗
PubMed2005

The clinical spectrum of thrombotic thrombocytopenic purpura.

The clinical syndrome of fever, neurologic abnormalities, renal impairment with laboratory findings of thrombocytopenic and microangiopathic hemolytic anemia is seen in thrombotic thrombocytopenic purpura (TTP) and a variety of disorders associated with thrombotic microangiopathy (TMA). With improved understanding of the pathogenesis of the perturbed metabolic pathway of von Willebrand factor in TTP, the classic Moschcowitz syndrome, now more accurately referred to as idiopathic TTP, can be distinguished from other TMAs. The distinguishing features are useful not only in providing an accurate diagnosis but also help to determine the best therapeutic strategy.

Anemia, Hemolytic↗
PubMed2004

Intravascular clotting activation and bleeding in patients with hematologic malignancies.

The association between thrombosis, bleeding and neoplastic disease is well recognized. There are distinctive features of the thrombotic and bleeding complications associated with specific hematologic malignancies. A number of procoagulants can initiate intravascular clotting including tissue factor, cancer procoagulant and interleukin-1. The hematologic malignancy most often associated with intravascular clotting and bleeding is acute promyelocytic leukemia. The pathogenesis of the life-threatening bleeding disorder associated with this uncommon subtype of acute myeloid leukemia (AML) is complex and involves disseminated intravascular coagulation, fibrinolysis and proteolysis. Both all-trans retinoic acid and arsenic trioxide result in relatively rapid resolution of the coagulopathy. Intravascular clotting may also be induced by hyperleukocytosis in AML and by the hyperviscosity syndrome observed in multiple myeloma and Waldenström's macroglobulinemia. In the setting of hematologic malignancies, when thromboembolic complications occur, the presence of comorbid thrombophilic conditions should be excluded. Abnormal platelet production and function contribute to the development of thrombosis in patients with myeloproliferative disorders. The Budd-Chiari syndrome may be observed in patients with myeloproliferative disorders. A number of medications have thrombogenic potential, including corticosteroids, thalidomide, L-asparaginase, all-trans retinoic acid and arsenic trioxide.

Anticoagulants↗
PubMed2004

Clopidogrel-associated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the Food and Drug Administration.

BACKGROUND AND PURPOSE: Since the 1999 identification of clopidogrel-associated thrombotic thrombocytopenic purpura (TTP) through independent active surveillance, subsequent cases have been identified by pharmaceutical suppliers of clopidogrel and the Food and Drug Administration (FDA). For cases of clopidogrel-associated TTP reported between 1998 to 2002, we evaluated the quality and timeliness of data from 3 reporting systems-independent active surveillance (n=13), pharmaceutical suppliers (n=24), and the FDA (n=13)-and identified prognostic factors associated with mortality. METHODS: This study assessed the completeness of information on TTP diagnosis, treatment response, and causality from the 3 reporting systems. In addition, predictors of mortality were identified through classification tree analysis. RESULTS: Completeness, timeliness, and certainty of diagnosis were best for cases obtained by active surveillance, intermediate for cases reported to the pharmaceutical supplier, and poorest for cases reported directly to the FDA. Clopidogrel had been used for </=2 weeks by 65%. The survival rate for patients with clopidogrel-associated TTP was 71.2%. Receipt of therapeutic plasma exchange within 3 days of onset of TTP increased the likelihood of survival (100% versus 27.3%, P<0.001). CONCLUSIONS: Compared with reports submitted by suppliers or the FDA, reports obtained through active surveillance provided timelier and more complete information. Clopidogrel-associated TTP often occurs within 2 weeks of drug initiation, occasionally relapses, and has a high mortality if not treated promptly.

Adult↗
PubMed2004

The thrombogenic effect of an inflammatory cytokine on trophoblasts from women with preeclampsia.

OBJECTIVE: This study was undertaken to investigate whether the increased thrombogenic potential of cytotrophoblastic cells of women with preeclampsia can be accounted for by increased rates of apoptosis. STUDY DESIGN: Cytotrophoblasts were isolated from the placenta of (a) nulliparous women without hypertensive disease who were delivered at term and (b) nulliparous women with preeclampsia. The cytotrophoblasts were identified by morphology, and cytokeratin and gonadotropin-releasing hormone positivity. The inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was added to cytotrophoblasts in vitro and incubated for 24 hours. Tissue factor antigen, activity, and amount of apoptosis were evaluated both before and after TNF-alpha stimulation. RESULTS: TNF-alpha simulation significantly increased tissue factor activity both in the cytotrophoblasts of women with (0.08 +/- 0.04 pmol/min/10 6 cells to 0.53 +/- 0.19 pmol/min/10 6 cells) and without (0.07 +/- 0.04 pmol/min/10 6 cells to 0.30 +/- 0.16 pmol/min/10 6 cells) preeclampsia. TNF-alpha stimulation of the cytotrophoblasts also significantly increased tissue factor antigen in the cytotrophoblasts of both groups of women (3.6 +/- 0.9 fmol/10 6 cells to 34.0 +/- 7.5 fmol/10 6 cells, and 7.5 +/- 1.4 fmol/10 6 cells to 25.4 +/- 2.2 fmol/10 6 cells, respectively). For both tissue factor antigen and activity, the magnitude of increase after stimulation was significantly greater in the preeclamptic cytotrophoblasts. In contrast, both normal and preeclamptic cytotrophoblasts showed similar increases in their apoptotic indices (approximately 2-fold) after induction by TNF-alpha. CONCLUSION: The greater response of tissue factor activity and antigen to TNF-alpha by preeclamptic cytotrophoblasts cannot be accounted for by the increase in apoptosis. These data suggest that preeclamptic cytotrophoblasts are inherently more thrombogenic and more sensitive to TNF-alpha stimulation.

Adult↗
PubMed2004

Anticoagulant drugs: an update.

Thromboembolic disorders continue to be a major cause of morbidity and mortality, resulting in an increased need for anticoagulant therapy. In recent years, new anticoagulant drugs have been developed at a rapid pace, prompted by the recognition of many undesirable properties of currently used agents, and by a greater knowledge of the active enzymatic sites of clotting factors. Furthermore, the structure of a thrombus is better understood, so that newer drugs can inhibit thrombin or Factor Xa not only on the surface of a thrombus, as in the case of heparin, but also the fibrin-bound thrombin or Factor Xa within the thrombus. These agents are usually small molecules synthesized on the basis of their inhibition of specific active sites in the respective coagulation factors. They possess many improved characteristics, such as greater efficacy and safety, oral administration, reliable pharmacokinetics, less need for laboratory monitoring and minimal interactions with other drugs and diet. Prominent among these are lepuridin (Refludan, Pfizer), fondaparinux (Arixtra, Sanofi-Synthelabo) and ximelagatran (Exanta, Astra Zeneca). However, these new drugs are still far from fulfilling the desired objectives. Most of them possess some but not all of the needed properties. Furthermore, many do not have specific antidotes for immediate reversal of their pharmacologic actions, and all are much more costly than conventional agents. Development of newer agents with properties closer to that of the ideal drug remains a challenge.

Anticoagulants↗
PubMed2003

Dissemination of information on potentially fatal adverse drug reactions for cancer drugs from 2000 to 2002: first results from the research on adverse drug events and reports project.

PURPOSE: To describe the clinical findings, occurrence rates, causality evidence, and dissemination media for serious cancer drug-associated adverse drug reactions (ADRs) reported in the postmarketing setting. METHODS: ADRs were termed serious if they resulted in death or severe organ failure. ADR information for oncology drugs from package insert (PI) revisions, so-called Dear Doctor letters, and journal articles was evaluated to identify serious ADRs reported from 2000 to 2002. Timing and content of information disseminated was assessed. RESULTS: Twenty-five serious ADRs associated with 22 oncology drugs were identified after approval. Approximately half of these serious ADRs are associated with drugs approved before 1995. ADRs were described in articles in medical journals (17 ADRs), PI revisions (18 ADRs), and Dear Doctor letters (12 ADRs). PI revisions occurred less than 1 year after peer-reviewed publication for four ADRs. These revisions often differed for similar ADRs that occurred with drugs of the same class. Five of the seven ADRs lacking PI changes occurred with off-label use, for which PI change is not recommended by US Food and Drug Administration (FDA) policy. No cancer drug was withdrawn from the market during the observation period. CONCLUSION: Our findings demonstrate that serious ADRs may be discovered as long as 36 years after a drug receives FDA approval. This suggests a need for continued vigilance and efficient strategies for dissemination of information about ADRs associated with cancer drugs.

Adverse Drug Reaction Reporting Systems↗
PubMed2003

Current concepts in the diagnosis and management of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura is a multisystem disease characterized by thrombocytopenia, hemolytic anemia, renal failure, fever, and neurologic abnormalities. Plasma exchange has revolutionized the outcome of this entity from a once fatal disease to a disease that potentially is cured or has prolonged remission. The understanding of the pathophysiology of TTP continues to evolve. Recently, investigators showed that a deficiency in a specific plasma protease responsible for cleaving vWf plays a crucial role in the familial form of TTP. This explains in part why patients usually respond to plasma exchange therapy. The identification of a mutation in a specific gene that belongs to the metalloproteinase family located at chromosome 9q34 could have important therapeutic implications. TTP can be induced by certain drugs, especially immunosuppressants, in the setting of bone marrow and solid organ transplantation. This disease also has been described in association with HIV, pregnancy, cancer, and chemotherapy. TTP remains an ideal example of how knowledge about the etiology of a disease can improve therapeutic interventions.

Diagnosis, Differential↗
PubMed2003

Hereditary and acquired defects in the fibrinolytic system associated with thrombosis.

The fibrinolytic system plays a pivotal role in the regulation of hemostasis and the prevention of thrombosis. There are no drugs that will increase the plasma fibrinolytic activity for a lasting duration to prevent thrombotic events effectively. Despite the ability of vasoactive agents such as nicotinic acid and metformin to release PA from the vessel wall, this therapeutic effect has not been evaluated adequately. The PAs are short-acting and indicated only for thrombolysis and not for prophylaxis. Future directions are directed at finding, agents that can enhance plasminogen activator release or inhibit PAW-1 activity. As there are multiple factors involved in the pathogenesis of thrombosis, there are a number of conditions in which abnormal fibrinolysis is only a contributory factor. Examples are seen in pregnancy, especially during puerperium, when the thromboembolic risk is at its highest. The levels of inhibitors of fibrinolysis. both PAI-1 and PAI-2, are also at their highest. Another example was seen recently in the antiphospholipid syndrome, where antibodies against Annexin II, a receptor for tPA, were found to be higher than in healthy controls. Thus, a thorough investigation into other hereditary and acquired risk factors for thrombosis is recommended.

Fibrinolysis↗
PubMed2003

Pathogenesis of increased risk of thrombosis in cancer.

Since the observations of Trousseau, not only has the association of cancer and thrombosis been widely recognized but its pathogenesis is now better understood. Attention to the tumor cell as an important source of procoagulants has also contributed to our knowledge of this problem. Tumor cells express tissue factor (TF) and a cancer procoagulant (CP). TF is dormant in the living cell. However, it is activated during apoptosis of the cell, initiating the coagulation cascade and leading to thrombin generation. Because increased apoptosis occurs during treatment with chemotherapeutic agents, hormones, radiation, and hematopoietic growth factors, as well as when there is rapid tumor proliferation, the thrombosis risk is heightened accordingly. These developments have obvious basic and clinical implications.

Apoptosis↗
PubMed2003

Hyperviscosity in polycythemia vera and other red cell abnormalities.

Thrombosis is a major cause of mortality and morbidity in polycythemia vera (PV). The wide range of thrombotic events reflects the complex picture in PV. There are multiple factors involved in thrombogenesis in this disease, including increased hematocrit, thrombocytosis, impaired fibrinolytic activity, platelet activation, leukocyte activation, endothelial damage, interactions between platelets and endothelium, various modalities of therapy, and increased in whole-blood viscosity. Among them, the increase in blood viscosity, and hence the impairment of blood flow, is the major factor. In this article, the role of hyperviscosity in PV is reviewed. A high hematocrit occurs under PV and many other conditions with abnormal red blood cell aggregation. The impaired capillary blood flow results in neurological manifestations and increased bleeding risk in PV. Thrombotic complications can also occur in both arteries and veins and manifest as stroke, myocardial infarction, deep vein thrombosis, or pulmonary embolism. The hemodynamic principle is aptly applied in the management of PV. The most important objective is the reduction of the patient's hematocrit.

Blood Viscosity↗
PubMed2003

Tumor microenvironment and hemorheological abnormalities.

This article reviews the various mechanisms in a malignant tumor that lead to hypoxia, production of tumor interstitial fluid, and rheological changes in its microenvironment. In addition, the associated procoagulant effects are described. The latter phenomenon is the result of complex and dynamic interplay among tumor cells, endothelial cells, circulating blood cells, and angiogenic, clotting, and hemorheological factors. The implications of these abnormalities on therapeutic approach are discussed.

Extracellular Fluid↗
PubMed2003

Rheological abnormalities and thromboembolic complications in heart disease: spontaneous echo contrast and red cell aggregation.

The role of abnormal rheological changes in the pathogenesis of thromboembolism has received much attention in recent years, especially in the field of cardiology. Such changes are sometimes seen in an echocardiogram as a smokelike haze known as spontaneous echo contrast (SEC). The presence and severity of SEC correlate with dilated cardiac chambers and the incidence of thromboembolic complications. It is caused by increased red cell aggregation and increased fibrinogen levels, both of which are known risk factors for thrombosis. Although not used clinically, measurements of red cell aggregation can be made in research settings. This can provide findings that give insight into factors causing increased red cell aggregation. A small series of patients with angina pectoris was studied with the Myrenne aggregometer for red cell aggregation. The results, which show correlation between the plasma fibrinogen and triglyceride levels, are presented. As yet, there are only a few therapeutic guidelines for the correction of abnormally high fibrinogen levels in patients at risk.

Blood Viscosity↗
PubMed2003

Correction of hyperviscosity by apheresis.

Therapeutic apheresis is an extracorporeal blood purification technique designed for the removal of either plasma (plasmapheresis) or cellular blood components (cytapheresis). One of the main indications for the use of apheresis is in the treatment of the hyperviscosity syndromes that can result from either the presence of abnormal plasma components, such as antibodies, immune complexes, paraproteins, and cryoglobulins, or the excessive increase in blood cells as seen in polycythemia, leukemias, and myeloproliferative diseases. Apheresis involves withdrawal of anticoagulated blood via a vascular catheter, separation of different blood components by either centrifugation or membrane filtration, removal of the undesired component, and reinfusion of the remaining components with replacement fluid into the patient. The centrifugal method can be intermittent or continuous, the latter being faster and fully automated, and is principally used in North America. The membrane filtration technique, mainly used in Europe and Japan, involves the filtration of blood by filters of different pore sizes. These are used sequentially in a process called double or cascade filtration, enabling removal of specific plasma pathogens without need for replacement fluids. In paraproteinemias, hyperviscosity syndrome is most commonly seen with Waldenström's macroglobulinemia, followed by immunoglobulin (Ig) A and IgG (3) multiple myeloma. Single plasmapheresis with one plasma volume replacement (about 3 L) usually results in a dramatic improvement in patients with macrogobulinemia because of its predominant intravascular distribution, whereas repeated plasmapheresis is necessary with other types of paraproteins. Cryofiltration apheresis using a high-capacity cryofilter is specific for the removal of cryoglobulins. In leukemias with hyperleukocytosis, there are no evidence-based guidelines for use of leukapheresis, but it is commonly initiated when white blood cells (WBC) are > 100,000/microL or even with lower counts if leukostasis symptoms are present, especially in acute myeloid leukemia. Erythrocytapheresis and plateletpheresis are mostly used in the acute management of symptomatic patients with polycythemia vera (PV), essential thrombocytosis, and sickle cell disease.

Blood Component Removal↗
PubMed2003

Bleeding and thrombosis in the cancer patient.

There is an increased risk not only of bleeding but also of thrombosis in the cancer patient. The double jeopardy creates an additional problem in their management and requires special attention. This review provides information on pathophysiology in the regulation of hemostasis, leading to bleeding and thrombotic complications. The process is complex with multiple factors being involved. In addition to the pathogenesis, a number of clinical syndromes, diagnostic methods and the management of hemostatic abnormalities in the cancer patient are presented. Potential effects of cancer treatment on these risks magnify the hazards encountered by the managing team. Wherever management is discussed, emphasis is placed on the scientific basis for the rationale of the therapeutic approach.

Disease Progression↗
PubMed2002

TTP/HUS occurring in a simultaneous pancreas/kidney transplant recipient after clopidogrel treatment: evidence of a nonimmunological etiology.

BACKGROUND: One recently reported thrombotic thrombocytopenia purpura/hemolytic uremic syndrome (TTP/HUS) case involved a patient who underwent simultaneous pancreas/kidney (SPK) transplant followed by pancreas rejection and clopidogrel treatment, an antiplatelet agent that has been associated with immunologically mediated TTP/HUS. We present a second case of TTP/HUS developing in an SPK recipient who was also receiving clopidogrel. METHODS: After a stroke, a 48-year-old male SPK transplant recipient received clopidogrel. Four months later, thrombosis and rejection of the transplanted pancreas occurred. One week after a pancreatectomy, TTP/HUS developed that resolved with clopidogrel and sirolimus discontinuation and lowering of the tacrolimus dose. RESULTS: A plasma sample revealed von Willebrand factor cleaving metalloproteinase activity, although no immunoglobulins to the protease were identified. The patient continues taking tacrolimus with normal renal function 1 year after the incident. DISCUSSION: Our findings suggest a nonimmunological etiology for TTP/HUS in clopidogrel-treated transplant recipients. Furthermore, mechanistic focused laboratory studies can facilitate interpretation of case report findings.

Calcineurin↗