Presented by Novo Nordisk
A Fine Balance: New Developments in Hemostasis and Thrombosis
Posted June 13, 2007
On June 13, 2007, the Academy convened a briefing for science writers on various aspects of hemostasis/thrombosis, the balance between blood clot formation and clot lysis.
Bruce Furie of Harvard Medical School summarized the complex interactions between procoagulant and anticoagulant forces. Mortimer Poncz of the University of Pennsylvania School of Medicine reviewed the role of platelets in hemostasis and thrombosis, highlighting several discoveries regarding platelet production and function.
Steven Steinhubl of the University of Kentucky College of Medicine focused on new and emerging anticoagulants. He also evaluated how antiplatelet agents are being used in the treatment and of prevention of thrombosis. Andrew Schafer, current president of the American Society of Hematology and chairman of the Department of Medicine at Weill Cornell Medical College, explored the recent controversy regarding erythropoietic stimulating agents and thrombotic risk. He also detailed how novel efforts to correct thrombocytopenia could potentially impact clinical practice in the prevention or correction of bleeding.
This conference and eBriefing were made possible with the support from:
Aspirin Therapy and Anti-Platelet Medications
MedicineNet.com discusses the benefits and risks of aspirin therapy and antiplatelet medications aimed at preventing and treating coronary and cerebral vascular disease.
The journal has organized this collection of its articles on hemostasis, thrombosis, and vascular biology.
Clinical and Applied Thrombosis/Hemostasis
A journal that has published hemostasis/thrombosis research since 2002.
FDA Alert on Erythropoiesis Stimulating Agents (ESA)
FDA issued this alert (PDF, 55 KB) to provide new safety information for erythropoiesis-stimulating agents (ESAs) [Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa)]. Analyses of four new studies in patients with cancer found a higher chance of serious and life-threatening side effects and/or death with the use of ESAs. See here for another update.
Hemophilia & Thrombosis Research Society
The HTRS is a tax-exempt research organization whose primary purpose is to facilitate basic science and clinical research endeavors specific to hemophilia and related coagulation disorders.
An animation created by McGraw-Hill publishers showing the formation of a blood clot.
Hereditary Blood Disorders, NCBDDD, CDC
CDC's Division of Blood Disorders works to prevent and reduce complications experienced by persons with certain hereditary blood disorders including bleeding disorders, thrombophilia, and thalassemia.
International Society on Thrombosis and Haemostasis
This organization works to advance science relating to thrombosis and abnormalities of hemostasis and vascular biology; to provide a forum for discussion; to encourage research; to foster the exchange of ideas through scientific meetings and publications; and to standardize nomenclature and methods.
Internet Stroke Center at Washington University
A presentation on the management of oral anticoagulant therapy.
Journal of Thrombosis and Haemostasis
Another journal focusing on research in this area, published by the International Society on Thrombosis and Haemostasis.
This Web site contains information on heart and blood vessel disorders and blood disorders.
National Heart Lung and Blood Institute
This branch of the National Institutes of Health fosters research on blood diseases and disorders and provides information about clinical trials.
Browse this site at the WebMD network clinical pharmacology on medications like Coumadin, Heparin, and other drugs for blood disorders.
The Thrombosis Interest Group of Canada—Cancer & Thrombosis
This Web site reviews the evidence of a link between cancer and thrombo-embolic disease.
Inherited bleeding disorders
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Hellström-Lindberg E, Willman C, Barrett A-J, Saunthararajah Y. 2000. Achievements in understanding and treatment of myelodysplastic syndromes. Hematology Am. Soc. Hematol. Educ. Program 1: 110-132. Full Text
Ariyo AA, Thach C, Tracy R, et al. 2003. Lp (a) Lipoprotein, vascular disease, and mortality in the elderly. N. Engl. J. Med. 349: 2108-2115.
Classic anticoagulant therapies
Ansell JE, Weitz JI, Comerota AJ. 2000. Advances in therapy and the management of antithrombotic drugs for venous thromboembolism. Hematology Am. Soc. Hematol. Educ. Program 1: 266-284. Full Text
Eriksson BI, Wille-Jørgensen P, Kälebo P, et al. 1997. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N. Engl. J. Med. 337: 1329-1335.
Ginsberg JA, Crowther MA, White RH, Ortel TL. 2001. Anticoagulation therapy. Hematology Am. Soc. Hematol. Educ. Program 1: 339-357. Full Text
Hirsh J, Heddle N, Kelton J. 2004. Treatment of heparin-induced thrombocytopenia: a critical review. Arch. Intern. Med. 164: 361-369.
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Antiplatelet therapies and procoagulants
Bergqvist D, Solhaug JH, Holmdahl L, et al. 2004. Pharmacokinetics, preliminary efficacy and safety of subcutaneous melagatran and oral ximelagatran: a multicentre study of thromboprophylaxis in elective abdominal surgery. Clin. Drug Investig. 24: 127-136.
Richardson PG, Elias AD, Krishnan A, et al. 1998. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 92: 737-744. Full Text
Yamasaki S, Masuhara K, Fuji T. 2005. Tranexamic acid reduces postoperative blood loss in cementless total hip arthroscopy. J. Bone Joint Surg. Am. 87: 766-770.
Emerging anticoagulant therapies
Bauer KA. 2006. New anticoagulants. Hematology Am. Soc. Hematol. Educ. Program 1: 450-456. Full Text
Cosmi B, Cini M, Legnani C, et al. 2003. Additive thrombin inhibition by fast moving heparin and dermatan sulfate explains the anticoagulant effect of sulodexide, a natural mixture of glycosaminoglycans. Throm. Res. 109: 333-339.
Eriksson BI, Dahl OE, Buller HR, et al. 2005. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized clinical trial. J. Thromb. Haemost. 31: 103–111. Full Text
Eriksson BI, Quinlan DJ. 2006. Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopaedic surgery. Drugs 66: 1411-1429.
Fisher WD, Eriksson BI, Bauer KA, et al. 2007. Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies. Thromb. Haemost. 97: 931-937.
Geerts WH, Pineo GF, Heit JA, et al. 2004. Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126: 338S-400S. Full Text
Ng HJ, Crowther MA. 2006. New anti-thrombotic agents: emphasis on hemorrhagic complications and their management. Semin. Hematol. 43: S77-S83.
Segal JB, Streiff MB, Hofmann LV, et al. 2007. Management of venous thromboembolism: a systematic review for a practice guideline. Ann. Intern. Med. 146: 211-222.
Weitz JI. 2006. Emerging anticoagulants for the treatment of venous thromboembolism. Thromb. Haemost. 96: 274-284.
Treatment advances in thrombocytopenia
Cines DB, Rauova L, Arepally G, et al. 2007. Heparin-induced thrombocytopenia: an autoimmune disorder regulated through dynamic autoantigen assembly/disassembly. J. Clin. Apher. 22: 31-36.
Das P, Ziada K, Steinhubl SR, et al. 2006. Heparin-induced thrombocytopenia and cardiovascular diseases. Am. Heart J. 152: 19-26.
Kuter DJ. 2007. New thrombopoietic growth factor. Blood 109: 4607-4616. (PDF, 276 KB) Full Text
Controversies in hemostasis and thrombosis
Bauer KA. 2007. Hypercoagulable disorders associated with malignancy. In: Rose BD (Ed), UpToDate, Wellesley, MA.
Bergqvist D, Agnelli G, Cohen AT, et al. 2002. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N. Engl. J. Med. 346: 975-980.
Blom JW, Doggen CJ, Osanto S, Rosendaal FR. 2005. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293: 715-722.
Campbell CL, Smyth S, Montalescot G, Steinhubl SR. 2007. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA 297: 2018-2024.
Danish Head and Neck Cancer Group. 2006. Interim analysis of DAHANCA 10. (PDF, 36 KB)
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Gomes MP, Deitcher SR. 2003. Diagnosis of venous thromboembolic disease in cancer patients. Oncology (Williston Park) 17: 126-35, 139.
Henke M, Laszig R, Rübe C, et al. 2003. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362: 1255-1260.
Henke M, Mattern D, Pepe M, et al. 2006. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J. Clin. Oncol. 24: 4708-4713.
Khorana AA, Francis CW, Culakova E, et al. 2006. Thromboembolism in hospitalized neutropenic cancer patients. J. Clin. Oncol. 24: 484-490. Full Text
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Lee AY, Levine MN. 1999. The thrombophilic state induced by therapeutic agents in the cancer patient. Semin. Thromb. Hemost. 25: 137-145.
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Piccioli A, Lensing AW, Prins MH, et al. 2004. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J. Thromb. Haemost. 2: 884-889. Full Text
Prandoni P, Lensing AWA, Piccioli A, Bernardi E. 2002. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 100:3484-3488.
Rosovsky RP, Kuter DJ. 2005. Catheter-related thrombosis in cancer patients: pathophysiology, diagnosis, and management. Hematol. Oncol. Clin. North Am. 19: 183-202, vii.
Singh AK, Szczech L, Tang KL, et al. 2006. Correction of anemia with epoetin alfa in chronic kidney disease. N. Engl. J. Med. 355: 2085-2098.
Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. 2000. Prognosis of cancers associated with venous thromboembolism. N. Engl. J. Med. 343: 1846-1850.
Sorensen HT, Mellemkjaer L, Steffensen FH, et al. 1998. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N. Engl. J. Med. 338: 1169-1173.
Wright JR, Ung YC, Julian JA, et al. 2007. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J. Clin. Oncol. 25: 1027-1032.
Zangari M, Anaissie E, Barlogie B, et al. 2001. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 98: 1614-1615. Full Text
Zwicker JI, Furie BC, Furie B. 2007. Cancer-associated thrombosis. Crit. Rev. Oncol. Hematol. 62: 126-136.
Bruce Furie, MD
Harvard Medical School
e-mail | web site | publications
Bruce Furie is a professor of medicine at Harvard Medical School and co-chief of the Division of Hemostasis and Thrombosis in the Department of Medicine of the Beth Israel Deaconess Medical Center in Boston. His past appointments include serving as chief of the Division of Hematology-Oncology at Tufts University School of Medicine and director of the Beth Israel Deaconess Cancer Center.
Furie's research interests focus within the area of hemostasis and thrombosis. Major activities in the laboratory involve the study of the structure-function relationships of the blood coagulation proteins, with special attention directed toward the vitamin K-dependent proteins; the assembly of Factor IX and Factor VIII on membrane surfaces; and the structural biology of proteins involved in blood coagulation. In addition, his laboratory discovered P-selectin, a cell adhesion molecule important to inflammation and thrombosis. The study of vascular cell adhesion molecules has remained a central theme of the laboratory. This group has also developed novel instrumentation for real time in vivo confocal and widefield imaging of thrombus formation in the microcirculation of a living mouse, and used these techniques to study the protein and cellular response to vessel wall injury during thrombosis.
Furie was the recipient of the William Dameshek Prize of the American Society of Hematology in 1984, a MERIT Award from the NIH, and an honorary degree from Lund University (Sweden) in 2003. He is coeditor of the hematology textbook, Hematology: Basic Principles and Practice, now going into its fifth edition, and lead editor of Clinical Hematology-Oncology: Presentations, Diagnosis, and Treatment. He serves as the president of the 2009 Congress of the International Society for Thrombosis and Haemostasis and is currently on the editorial boards of Blood, the Journal of Thrombosis and Haemostasis, and Molecular Medicine.
Mortimer Poncz, MD
University of Pennsylvania School of Medicine
e-mail | web site | publications
Mortimer Poncz has worked as professor of pediatrics at the University of Pennsylvania School of Medicine since 1992, and is division chief of hematology at the Children's Hospital of Philadelphia. He is an NIH-funded investigator with over 110 peer-reviewed publications related to hemostasis and thrombosis with an emphasis on platelet biology. In recent research he has worked to define the pathogenesis of a clinical thrombotic disorder, Heparin-Induced Thrombocytopenia (HIT); to use platelets as a strategy for targeted delivery of ectopic proteins to a site of thrombosis; and to understand the role of negative regulators in megakaryopoiesis and platelet formation. He has also served as associate editor of Blood since 2002.
Andrew I. Schafer, MD
Weill Cornell Medical College
e-mail | web site | publications
Andrew Schafer completed his medical education at the University of Pennsylvania, his internal medicine residency at the University of Chicago, and his fellowship in hematology at the Peter Bent Brigham (now Brigham and Woman's) Hospital and Harvard Medical School. After rising through the ranks at Harvard to associate professor of medicine, he moved to Houston in 1989 to become chief of medicine of the Houston VA Medical Center and then chairman of the Department of Medicine at Baylor College of Medicine. In 2002 he became the Frank Wister Thomas Professor and Chairman of the Department of Medicine at the University of Pennsylvania. He assumed his current position in May 2007 as the E. Hugh Luckey Distinguished Professor and Chairman of the Department of Medicine at Weill-Cornell Medical College and physician-in-chief of the New York Presbyterian Hospital–Weill Cornell Medical Center.
Schafer is the author of over 200 original articles and the editor of five textbooks in the field of hemostasis, thrombosis, and hematology. He also made original contributions to our understanding of normal platelet biology and metabolism, abnormalities of platelet function in the myeloproliferative disorders, platelet–vascular call interactions, the role of hemodynamic forces on platelets and vascular endothelial and smooth muscle cells, and the nitric oxide synthase/nitric oxide and the heme oxygenase/carbon monoxide systems in vascular cell biology. He has been the principal investigator of NIH grants for almost 30 consecutive years, and serves on the board of extramural advisors of the NHLBI.
Schafer has been elected to membership in the American Society for Clinical Investigation (for which he served as secretary-treasurer) and in the Association of American Physicians, and fellowship in the American Association for the Advancement of Science. He is on the board of directors of the Association of Professors of Medicine, and is currently president of the American Society of Hematology.
Steven R. Steinhubl, MD
University of Kentucky
e-mail | web site | publications
Steven Steinhubl is associate professor of medicine and the director of the Cardiovascular Education and Clinical Research at the University of Kentucky in Lexington. His research activities cover a broad range of topics in cardiology, with a primary focus on antithrombotic therapies in acute coronary syndromes and percutaneous coronary interventions, inflammation, and variability in response to antiplatelet therapies. He has been principal investigator of the CREDO and GOLD trials, and is currently principal investigator of the several phase I trials as well as co-principal investigator for the STEEPLE trial and co-chairman of the ACUITY Inflammation sub-study. He is also a member of the steering committees for the STRADIVARIUS, SYNERGY, EVENT, CATCH, and CHARISMA trials, and a national coordinator for CRESCENDO. He is a member of the editorial boards for theheart.org, the American Heart Journal, and the Journal of the American College of Cardiology, and an editor-in-chief of Acute Coronary Syndromes.
Steinhubl received his undergraduate training in chemical engineering at Purdue University, graduate training in physiology at Georgetown University, and his medical degree at St. Louis University. His internal medicine residency training was completed at David Grant Medical Center at Travis Air Force Base, California. Following residency, he was a staff internist at Elmendorf Air Force Base Hospital in Anchorage, Alaska, where he was also the associate chief of medicine and director of the Cardiopulmonary Laboratory. He completed cardiology and interventional cardiology fellowships at the Cleveland Clinic Foundation, where he was also chief cardiology fellow. Prior to joining the University of Kentucky faculty, Steinhubl was a staff cardiologist at Wilford Hall USAF Medical Center in San Antonio, Texas, and then associate director of the Cardiac Catheterization Laboratory at the University of North Carolina.
George Lundberg, MD
George Lundberg is editor-in-chief of MedGenMed, an online publication of Medscape. He also serves as editor-in-chief of Medscape Core and, since 2006, as editor-in-chief of eMedicine. A frequent lecturer, radio and television guest, and a member of the Institute of Medicine of the National Academy of Sciences, Lundberg holds academic appointments as a professor at Stanford and Harvard.
Lundberg became editor-in-chief of Medscape in 1999 and the founding editor-in-chief of both Medscape General Medicine and CBS HealthWatch.com. In 2002, Lundberg became special healthcare advisor to the chairman and CEO of WebMD. He is past president of the American Society of Clinical Pathologists. From 1982 to 1999, he was editor-in-chief of scientific information and multimedia at the American Medical Association, with editorial responsibility for its 39 medical journals, American Medical News, and various Internet products. He was also the editor of the Journal of the American Medical Association.
Lundberg holds earned and honorary degrees from North Park College, Baylor University, the University of Alabama (Birmingham and Tuscaloosa), the State University of New York, Syracuse, Thomas Jefferson University, and the Medical College of Ohio. He completed a clinical internship in Hawaii and a pathology residency in San Antonio. He served in the U.S. Army during the Vietnam War in San Francisco and El Paso, leaving as a lieutenant colonel after 11 years. He was then professor of pathology and associate director of laboratories at the Los Angeles County/USC Medical Center for 10 years, and for five years was Professor and Chair of Pathology at the University of California-Davis. Lundberg has worked in tropical medicine in Central America and forensic medicine in New York, Sweden, and England. His major professional interests are toxicology, violence, communication, physician behavior, strategic management, and health system reform.
Robert Mocharnuk, MD, is an instructor of clinical hematology at the Los Angeles County and University of Southern California Medical Center. He earned his MD at Texas Tech University before completing internships, residencies, and fellowships at LAC+USC. He is board certified in internal medicine and medical oncology, and focuses on clinical medicine and hematology.
In simplistic terms, the human body can be thought of as a well-balanced machine of opposing forces. For example, cellular formation is opposed by cellular destruction. Similarly, hemostasis represents the balance between clot formation and clot lysis to prevent hemorrhage without causing thrombosis, the partial or complete blockage of blood vessels. Anything that disrupts this system predisposes the individual to either bleeding or clotting. There are a number of components involved in the hemostatic process, and problems with any of these components can lead to serious disruptions in an individual's ability to regulate bleeding or clotting. These components include blood vessel walls, inclusive of endothelial cells and subendothelial constituents; coagulation factors and inhibitors; platelets; and the various factors that make up the fibrinolytic system.
When a blood vessel is injured, the exposure of subendothelial tissues leads to platelet aggregation. Platelets are anchored to the endotheilial lining through the mediation of von Willebrand's factor. Once bound, the platelets are activated, resulting in the release of cytoplasmic granules that further promote platelet aggregation. The injured subendothelium also releases tissue factor, which in turn activates a number of coagulation factors, ultimately resulting in the cleaving of prothrombin to thrombin. Thrombin then cleaves the circulating plasma protein fibrinogen to form fibrin, an insoluble meshwork that stabilizes existing platelet plugs to which additional platelets can anchor.
The system of blood clot formation and lysis is a well-balanced machine, and problems in any of its components can be life-threatening.
To prevent clotting from occurring randomly throughout the circulatory system, small amounts of coagulation factor inhibitors travel throughout the bloodstream, inactivating procoagulant factors. Only at sites of injury do procoagulant factors outweigh anticoagulant factors, thereby confining the scope of clot formation. Within the fibrinolytic system, clot lysis is achieved by the direct action of the protease plasmin, which is activated through proteolytic cleavage of its inactive zymogen, plasminogen. The known activators of plasminogen are tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). The serine protease inhibitors α2-antiplasmin (α2AP) and plasminogen activator inhibitors (PAIs) target plasmin as well as tPA and uPA. Cellular receptors for uPA (uPAR), tPA, and plasmin, in concert with other components of the fibrinolytic system, serve to localize and fine-tune the process of clot lysis.
While simplistic, this explanation highlights the fact that normal hemostasis can be easily disrupted by both quantitative and qualitative changes in any of the components involved in clot formation or clot lysis.
On June 13, 2007, the New York Academy of Sciences convened a briefing for science writers, featuring four noted hematology experts who focused on various aspects of hemostasis/thrombosis and provided insights into recent advances that are being made in this field. This event and eBriefing were made possible by an unrestricted grant from Novo Nordisk.
The event was moderated by George Lundberg, editor-in-chief of Medscape's MedGenMed electronic journal. He was joined by the following four speakers:
Bruce Furie, professor of medicine at Harvard Medical School, set the stage by summarizing the complex interactions between procoagulant and anticoagulant forces.
Mortimer Poncz, professor of medicine in the Pediatrics Division of Hematology at the University of Pennsylvania School of Medicine, reviewed the role of platelets in hemostasis and thrombosis, highlighting several interesting discoveries regarding platelet production and function.
Steven Steinhubl, associate professor of medicine at the University of Kentucky College of Medicine, focused on new and emerging anticoagulants that it is hoped will overcome some of the limitations of current anticoagulation therapy. Steinhubl also evaluated how antiplatelet agents are being used in the treatment and of prevention of thrombosis.
Andrew Schafer, current president of the American Society of Hematology and chairman of the Department of Medicine at Weill Cornell Medical College, explored the recent controversy regarding erythropoietic stimulating agents and thrombotic risk. He also detailed how novel efforts to correct thrombocytopenia could potentially impact clinical practice in the prevention or correction of bleeding.
This special eBriefing contains an overview of the state of the art in clinical research and drug development related to hemostasis and thrombosis. Multimedia presentations including slides and audio of each of the speakers' talks are also available.
Robert Mocharnuk, MD, is an instructor of clinical hematology at the Los Angeles County and University of Southern California Medical Center.
Inherited bleeding disorders
Bleeding or clotting disorders are either inherited or acquired. Von Willebrand's disease, the most commonly inherited bleeding disorder with an estimated incidence as high as 1 in 100 to 1 in 1000, occurs because of either a qualitative or a quantitative defect in von Willebrand's factor. Von Willebrand's factor is a variable-length polymer of a glycoprotein that facilitates platelet adhesion between receptors on the surface of platelets and the subendothelial lining of blood vessels. In addition, von Willebrand's factor serves as a carrier for clotting Factor VIII, extending its half-life from 8 minutes to over 8 hours.
The most commonly inherited clotting factor disorders are deficiencies in Factors VIII, IX, and XI, of which the most common is Factor VIII deficiency, also known as hemophilia A. The inherited form of Factor VIII deficiency is found on the X chromosome, thereby ensuring that this disease affects males almost exclusively since males only carry one copy of the X chromosome. It is estimated that 1 in 5000 males is born with Factor VIII deficiency. Severe hemophilia A is rare in females, occurring in less than 1 in 1,000,000 individuals.
Factor IX, known as hemophilia B, is also X-linked, and is estimated to occur in 1 of every 30,000 male births. Autosomal recessive Factor XI deficiencies are much rarer, occurring in 1 of every 500,000 births, although the incidence in Ashkenazi Jews is much higher. Other inherited clotting factor disorders are extremely rare, and include a number of different Factor I deficiencies (categorized as afibrinogenemias, hypofibrinogenemias, or dysfibrinogenemias), Factor II prothrombin deficiencies, and deficiencies in Factors V, X, and XIII.
Inherited functional platelet disorders are also quite rare, but can lead to serious bleeding in affected individuals:
Bernard-Soulier syndrome, a disorder of platelet adhesion, represents a deficiency of platelet glycoprotein Ib/IX, a receptor complex that binds platelets to von Willebrand's factor on the subendothelial surface of blood vessels.
Glanzmann's thrombasthenia results from a deficiency of the glycoprotein IIb/IIIa complex, preventing platelets from interacting or aggregating with other platelets to form a plug at the site of injury. Following platelet activation, intracytoplasmic granules release substances vital to platelet plug formation and maintenance. Absent or defective thromboxane A2 receptors prevent the binding of thromboxane that is necessary for platelet granule release. Researchers have also described defects in the enzyme that converts arachidonic acid to thromboxane that result in thromboxane deficiency.
Disorders inherent to platelet granules include alpha granule deficiency (known as gray platelet syndrome) and dense or delta granule deficiency (e.g., Hermansky-Pudlak syndrome and Chediak-Higashi syndrome). Platelet receptor signaling defects following binding of an agonist to the platelet surface receptor inhibit the secondary changes within the platelet that cause the granules to release their contents, as in Wiskott-Aldrich syndrome. Quebec platelet disorder is due to expression of uPA in platelet alpha granules. These patients have bleeding with surgery, and do not respond to platelet transfusions but do respond to anti-fibrinolytic agents.
Defective platelet procoagulant activity (Scott syndrome) is an extremely rare disorder caused by impaired exposure of phosphatidylserine on the outer layer of the platelet membrane. After platelet activation a surface is formed that is conducive for coagulation events to occur for generating thrombin. In particular, a decrease in this activity, also called platelet factor 3 activity, results in fewer Factor Va and Factor Xa binding sites, with severe bleeding as an end result.
Decreased platelet production can also be an inherited condition that predisposes individuals to bleeding. Bernard-Soulier syndrome, the May-Hegglin syndrome (which results from mutations in the cytoskeletal MYH9 protein, and consists of a triad of thrombocytopenia, giant platelets, and leukocytic inclusions, causing variable hearing, heart, and renal defects), as well as Wiskott-Aldrich syndrome, are associated with decreased platelet production. Thrombocytopenia is also characteristic of the recently recognized family platelet deficiency/acute myeloid leukemia (FPD/AML) syndrome.
Inherited connective tissue disorders such as Marfan's syndrome and Ehlers-Danlos syndrome produce abnormal collagen, resulting in blood vessel fragility that manifests as easy bruising or bleeding. Cavernous hemangiomas and hereditary hemorrhagic telangiectasia are both characterized by blood vessel wall defects that can also result in significant bleeding.
Congenital deficiency of plasminogen is also associated with a clinical syndrome previously known as ligneous conjunctivitis, a predominantly ocular disorder. Surprisingly, these patients do not develop widespread vascular thrombosis, suggesting that alternative mechanisms for clot lysis and fibrin clearance may exist in humans. Congenital deficiency states for α2AP and PAI-1 have also been described, and such patients develop mild to moderate bleeding, particularly after trauma.
Acquired bleeding disorders
The number of acquired bleeding disorders far exceeds the number of inherited ones. Acquired bleeding disorders occur because of platelet deficiency or dysfunction, coagulation factor deficiency or dysfunction, or structural problems with blood vessels.
There are a number of reasons for acquired platelet dysfunction. In very broad terms, thrombocytopenia occurs when the bone marrow fails to produce enough platelets (due to marrow-based malignant and non-malignant conditions such as aplastic anemia, acute and chronic leukemias, multiple myleoma, myelophthysis from marrow infiltration by solid tumor cells, myelodysplasia, myelofibrosis); when platelets are destroyed in the peripheral circulation secondary to drugs, anatomic conditions, autoimmune conditions, HIV and other viral illnesses, or bacterial toxins; when platelets are activated excessively, as in cardiopulmonary bypass or disseminated intravascular coagulation (DIC); when patients receive massive transfusions of red blood cells or whole blood without platelet replacement; when platelets are sequestered due to hypersplenism; and when platelets are rendered ineffective by drugs, renal disease, or liver disease.
Bleeding disorders that arise from acquired coagulation factor deficiencies or dysfunction are seen in liver disease, vitamin K deficiency states, fat malabsorption syndromes, autoimmune conditions that produce factor inhibitors, DIC, and with use of anticoagulant therapy and certain types of chemotherapy. Snake venom and bacterial toxins can also function as anticoagulants.
Acquired blood vessel disorders include allergic purpura, an autoimmune condition in which small blood vessels become inflamed, leading to vessel leakage. In addition, trauma can lead to massive loss of blood that far exceeds the body's ability to produce new clotting factors or platelets.
Inherited thrombotic disorders
Clotting disorders, like bleeding disorders, can be inherited as well as acquired. Inherited gene mutations that predispose individuals to thrombosis include factor V Leiden protein C resistance and the prothrombin G20210A mutation. Other inherited hypercoagulable disorders include protein C deficiency or dysfunction, protein S deficiency or dysfunction, antithrombin (also known as antithrombin III) deficiency or dysfunction, elevated Factor VIII levels, and hyperhomocysteinemia.
Except for antithrombin deficiency, all of the inherited prothrombotic disorders can be either heterozygous (one gene copy mutation) or homozygous (two gene copy mutations). While not universally true, homozygous mutations tend to produce more severe clinical effects, while multiple heterozygous mutations in different clotting components can multiply the effects of the individual genetic deficiencies. Individuals with inherited clotting disorders often have a family history of thrombosis, thrombosis occuring in atypical sites, and first thrombotic episodes before the age of 40.
Both inherited and acquired defects in the fibrinolytic system are responsible for clot breakdown disorders. There are at least six types of congenital plasminogen disorders, all of them quite rare. There are also disorders of plasminogen activators, as well as plasminogen activator inhibitors. High levels of the former predispose patients to hemorrhage while low levels reduce fibrinolysis and increase the risk of thrombosis. Likewise, increased levels of plasminogen activator inhibitors have been observed in pregnancy, sepsis, and after myocardial infarctions and deep venous thrombosis. Decreased levels of plasminogen activator inhibitors have been ascribed to a rare autosomal recessive disorder in which patients tend to bleed. Qualitative and quantitative dysfibrinogenemias, primarily acquired but rarely congenital, have also been described in individuals with both thrombotic and bleeding tendencies.
Congenital overexpression of lipoprotein a, which occurs more commonly in African Americans than in Caucasians, is responsible for competitively displacing plasminogen from binding sites on both fibrin and endothelial cells, thereby preventing activation of tissue plasminogen activator (TPA) while increasing tissue plasminogen activator inhibitor (PAI-1) levels. The net result is to promote thrombosis and inhibit fibrinolysis.
Acquired thrombotic disorders
As with bleeding disorders, acquired clotting disorders are more common than inherited ones. Acquired clotting disorders can stem from blood vessel defects caused by atherosclerosis—the accumulation of cholesterol-lipid-calcium deposits in the walls of arteries—as well as by autoimmune vasculitis that inflames blood vessel walls, producing platelet adhesion and coagulation factor activation. Any condition that immobilizes an individual for a long period of time—flying in coach class, prolonged bed rest due to illness or surgery—can produce slow or restricted blood flow, particularly in the deep veins of the legs. Heart failure, recent surgery, obesity, pregnancy, oral contraceptive use, hormone replacement therapy, atrial fibrillation with rapid heart beat, malignancies (known as Trousseau's syndrome), and radiation or chemotherapy for treatment of malignancies have all been linked to an increase in the risk of thrombosis.
Individuals, particularly those with underlying autoimmune disease, can also acquire antiphospholipid and anticardiolipin antibodies, which predispose them to both arterial and venous thrombosis as well as an increased risk of miscarriage. Similarly, acquired defects in the enzymes that metabolize homocysteine can result in hyperhomocysteinemia, which increases the risk of both arterial and venous thrombosis.
As mentioned previously, acquired defects in the fibrinolytic system responsible for clot lysis can predispose patients to thrombosis. In particular, individuals can acquire dysfibrinogenemias, as well as defects or deficiencies in plasminogen, plasminogen activators, and plasminogen activator inhibitors. The most common causes of these disorders include DIC, liver therapy, and iatrogenic use of fibrinolytic therapies.
The hematologist's toolbox
A variety of laboratory tests is available to assist the clinician in diagnosing various bleeding and clotting disorders. The complete blood count (CBC) is the most commonly ordered test and provides data regarding platelet number, but not functionality. The prothrombin time (PT) assesses the extrinsic and common coagulation pathways that includes Factors I, II, V, VII, and X. Prolongation of this test indicates the presence of a factor deficiency, a factor inhibitor, or use of oral anticoagulant therapy. The activated partial thromboplastin time (APTT) measures the recalcification time of plasma after incubation with phospholipid and the mineral kaolin, and is used to assess the coagulation factors of the intrinsic and common coagulation pathway, including Factors I, II, V, X, VIII, IX, XI, and XII. Prolongation of this test occurs with factor deficiencies, factor inhibitors, antiphospholipid antibodies (i.e., lupus anticoagulant), or use of heparin. Note that neither the PT nor APTT measures Factor XIII deficiency and if this is suspected then a specific test for this factor must be done.
To determine whether a prolonged PT or APTT is due to a factor inhibitor or a factor deficiency, a mixing study can be performed in which patient plasma and normal control plasma samples are combined in specific ratios. Failure of the PT to correct with normal patient plasma indicates the presence of a factor inhibitor. Failure of the APTT to correct with normal patient plasma indicates the presence of a factor inhibitor or a lupus anticoagulant, the latter of which binds to phospholipids and proteins, preventing the normal interaction between these components and the cell membrane.
Since the APTT depends on the presence of phospholipids to induce clotting, anything that inhibits or neutralizes phospholipids will prolong the APTT. However, a normal APTT does not necessarily rule out the presence of an antiphospholipid antibody, and many affected patients, especially pregnant women, have normal APTTs.
Factor deficiencies can be assessed by measuring the activity of the individual clotting factors, whereas inhibitors can be measured by assessing the titers of specific clotting factor inhibitors. If a lupus anticoagulant is suspected, a dilute Russell viper venom test (dRVVT) or kaolin clotting time is recommended as a confirmatory study. Venom from the highly poisonous Russell viper directly activates factor X in patient plasma. Therefore, deficiencies or inhibitors of Factor VII, VIII, IX, XI, and XII, do not affect the dRVVT. Dilution of the Russell viper venom reagent ensures that the phospholipid concentration will be low, thus increasing the sensitivity for detection of antiphospholipid antibodies.
In the kaolin clotting time assay, negatively-charged kaolin is incubated with patient plasma to activate both contact and intrinsic clotting factors. Unlike the dRVVT or APTT assays, the kaolin clotting time depends on the presence of plasma rather than reagent-added phospholipids. Therefore, the kaolin clotting time will be prolonged in the presence of an antiphospholipid antibody.
The tissue thromboplastin inhibition time (TTIT) is another APTT-type assay that uses a dilute thromboplastin reagent as the source of phospholipid. Patient plasma is incubated with a dilute thromboplastin reagent and the clotting time is then calculated. This result is compared with the same result from pooled normal plasma. If the clotting time ratio for the patient plasma is greater than 1.2 compared with the clotting time of the pooled normal plasma, there is likely an antiphospholipid antibody present.
The hexagonal phase phospholipid neutralization test is the most sensitive and specific confirmatory assay for detecting lupus-like inhibitors. In this test, the addition of hexagonal phase phospholipids induces binding of antiphospholipid antibodies, thereby neutralizing their effect on the normal APTT, while preserving the effect of factor-specific inhibitors.
All four tests—the dRVVT, the TTIT, the hexagonal phase neutralization assay, and the kaolin clotting time—are affected by the presence of platelet-rich plasma, which contains high levels of phospholipid. In addition, the presence of heparin can confound all four of these test results, while coumadin prolongs dRRVT results.
Once the presence of a lupus anticoagulant has been confirmed, specific assays exist to determine whether the antiphospholipid antibody is an anticardiolipin antibody, a β-2 glycoprotein I antibody, an antiphosphatidylserine antibody, or a prothrombin antibody.
The thrombin time is used to measure the rate at which fibrinogen is converted to fibrin when a small amount of thrombin is added to a patient plasma sample. Thrombin time prolongation can be caused by elevated levels of fibrin/fibrinogen degradation products (FDPs), hereditary or acquired fibrinogen abnormalities including hypofibrinogenemia or dysfibrinogenemia), or the presence of heparin or fibrinolytic agents such as streptokinase or urokinase. A reptilase test can be used to correct for heparin exposure.
Levels of the fibrinolysis inhibitor α-2-antiplasmin are reduced in hereditary α-2-antiplasmin deficiency, a rare autosomal recessive bleeding disorder. Acquired α-2-antiplasmin deficiency is found in patients with liver disease, disseminated intravascular coagulation (DIC), and in those receiving thrombolytic therapy.
The bleeding time is a controversial test whose accuracy is operator-dependent. Here, a precise incision of specific length and depth is made in the skin and the time until the bleeding stops is measured. For years, the bleeding time was used as a presurgical screening tool for assessing bleeding risk. The bleeding time is not sensitive or specific, and it does not necessarily reflect the risk or severity of surgical bleeding. It also leaves small scars on patient's forearms. The most common causes of prolonged bleeding times are von Willebrand's disease, medication-induced platelet dysfunction (aspirin, clopidogrel, abiciximab, eptifibatide, ticlopidine, dipyridamole, etc.), and platelet counts of less than 100,000/µL. In most hospitals and academic institutions, the bleeding time test has been largely replaced by the platelet function analyzer.
The platelet function analyzer measures the adherence and aggregation properties of platelets by exposing whole blood to collagen, epinephrine, and adenosine diphosphate (ADP). Other assays can detect platelet dysfunction secondary to aspirin ingestion while additional tests can monitor abciximab and eptifibatide anti-platelet therapy. Thromboelastography on whole blood measures the rapidity and strength of clot formation and is being used with increasing frequency in the arena of cardiovascular surgery to monitor platelet function and coagulation.
Testing for von Willebrand's factor deficiency includes measuring APTT, von Willebrand's antigen as well as activity levels, performing a multimer analysis to determine which size multimers are lacking, determining whether Factor VIII levels are low, and confirming the deficiency with ristocetin cofactor agglutination. Ristocetin cofactor, a negatively charged antibiotic, induces platelet agglutination in the presence of von Willebrand's factor. Conversely, a lack of agglutination or clumping implies that there is a qualitative or quantitative lack of von Willebrand's factor.
The euglobulin clot lysis time test measures the breakdown of the fibrin clot. Patient plasma is acidified and the "euglobulin" portion containing fibrinogen, plasminogen, plasminogen activators, and plasmin precipitates. This precipitate is then dissolved and thrombin is added to form a clot. Rapid clot lysis of less than 120 minutes is indicative of fibrinolysis, which can be secondary to DIC, or primary to liver disease or malignancy.
For patients with suspected DIC, standard work-up includes measuring the quantity of fibrinogen and the degradation products of fibrin. Fibrin degradation products (FDPs), also known as fibrin split products (FSPs) are formed from the breakdown of fibrin by plasmin and other fibrinolytic enzymes. However, measuring FDPs is not specific for DIC because it detects both soluble and cross-linked fibrin. Therefore, it does not differentiate whether fibrin is being generated by clot formation or by inflammation. Monoclonal antibody measurement of D-dimers, the breakdown products of a fibrin clot that has been stabilized by the presence of Factor XIII, is more specific to DIC because Factor XIII is activated only in the presence of liver disease, venous thromboembolism, DIC, or rheumatoid factor.
Finally, patients with a history of thrombosis and no precipitating factors should be screened for a hypercoagulable state that includes assessing protein C, protein S, and anti-thrombin III levels; screening for antiphospholipid and anticardiolipin antibodies; measuring Factor VIII activity and serum homocysteine; assaying for Factor V Leiden protein C resistance or the prothrombin gene mutation G20210A; and measuring lipoprotein "a" levels.
Classic anticoagulant therapies
The mainstays of anticoagulant therapy include unfractionated heparin, low molecular weight heparin (LMWH), and oral warfarin. Heparin is manufactured from pig intestines or bovine lung. It activates antithrombin, which blocks Factor Xa, Factor IXa, Factor IIa (thrombin), as well as Factors XIIa, XIa, and the Factor VIIa complex. Heparin must be administered subcutaneously or intravenously and is readily reversible with protamine sulfate or discontinuation of therapy, due to its short half-life of one hour.
Besides increasing the risk of bleeding, heparin can also induce thrombocytopenia. Type I heparin-induced thrombocytopenia (HIT) occurs in approximately 10%–20% of patients who receive unfractionated heparin. The platelet counts rarely fall below 100,000/µL, and no heparin-associated platelet antibodies are produced, suggesting that this is unlikely to be an immunogenic process. Type II HIT, on the other hand, develops in approximately 3% of patients receiving unfractionated heparin and can result in thrombosis in approximately 30%–40% of patients. Type II HIT appears to be mediated by antibody formation against the heparin/platelet factor 4 (PF4) complex located on the platelet surface.
Danaparoid is the only heparinoid approved by the U.S. Food and Drug Administration. Danaparoid is structurally distinct from heparin and LMWH and is therefore less likely to cause HIT, although some cases of HIT have been reported with use of this agent. Danaparoid inhibits Factor Xa to a greater degree than either heparin or LMWH. However, because of shortages of necessary components for manufacture of this product, danaparoid production was discontinued in August 2002.
LMWH has a number of advantages over unfractionated heparin. LMWH is more targeted than regular heparin in its effect, only accelerating anti-thrombin III's inactivation of Factor Xa, and is much less immunogenic than unfractionated heparin. Accordingly, the incidence of HIT is estimated to be 0.1%. In addition, LMWH does not require APTT monitoring since the plasma levels of these drugs are much more predictable, although many institutions having begun to measure plasma anti-Factor Xa activity for LMWH activity. However, LMWH also has certain disadvantages in that its plasma half-life is two- to four-fold longer than unfractionated heparin and cannot be reversed by protamine sulfate. Low molecular weight heparins currently approved in the United States include enoxaparin, tinzaparin, dalteparin, and ardeparin. A number of other LMWHs that have either already been approved in Europe and/or are under study in this country include bemiparin, nadroparin, parnaparin, reviparin, and sulodexide.
Warfarin, the only oral anticoagulant currently approved in the United States, inhibits the synthesis of vitamin K-dependent coagulation factors. To prevent warfarin-associated skin necrosis reactions, patients for whom anticoagulation therapy is indicated are started on heparin concurrently with warfarin until the warfarin level is therapeutic, at which time heparin therapy is discontinued. Warfarin's long plasma half-life of 40 hours means that it takes several days before serum levels are therapeutic. In addition, the protracted half-life of warfarin makes it much more difficult to reverse its anticoagulant effects. Warfarin levels can be markedly affected by dietary vitamin K intake, and monitoring on a frequent basis of warfarin effect is mandatory.
The immunogenic potential of both unfractionated heparin and LMWHs created the need for alternative anticoagulant therapies. Accordingly, a number of direct thrombin inhibitors, as well as inhibitors of Factor X were developed, each with its own unique properties and restrictions. Recombinant huridin (lepirudin) binds irreversibly with thrombin and has a plasma half-life of one hour. Since the drug is eliminated by the kidneys, dose adjustments are required for patients with impaired renal function. Lepirudin was the first direct thrombin inhibitor to be approved by the FDA for anticoagulation of patients with HIT. Argaroban, a synthetic L-arginine derivate, is a reversible thrombin inhibitor. It is metabolized by the liver and is therefore contraindicated in patients with severe liver dysfunction. Its half-life is approximately 45 minutes. Like lepirudin, argatroban is also approved for anticoagulation of individuals with HIT.
Bivalirudin is also a reversible direct thrombin inhibitor that has been approved by the FDA for use in percutaneous coronary interventions for unstable angina, prevention of thrombosis, and prophylaxis/treatment of HIT. Like lepirudin and argatroban, bivalirudin is administered intravenously and has a plasma half-life of ~25 minutes.
Desirudin was approved by the FDA in 2003 as the only direct thrombin inhibitor for prophylaxis against DVT and PE in patients undergoing hip surgery, based on studies showing a 27% reduction in the risk of VTE compared with enoxaparin.
Fondaparinux is a synthetic pentasaccharide that binds to antithrombin and selectively inhibits Factor Xa. Unlike lepirudin, argatroban, and bivalirudin, fondaparinux does not activate thrombin and therefore, has no known effect on platelet function. Fondaparinux is administered subcutaneously, is excreted by the kidneys, and is indicated for prevention and treatment of VTE. Efficacy is measured by monitoring anti-Factor Xa activity.
A host of antiplatelet therapies that prevent platelet aggregation or agglutination have been developed for individuals with an assortment of vascular diseases ranging from thrombotic strokes to coronary artery disease to claudication. There are three types of antiplatelet agents: aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors. Aspirin, the oldest of these agents, irreversibly inhibits the enzyme cyclo-oxygenase-1 (COX-1) responsible for producing thromboxane A-2 that plays a role in platelet activation. Picotamide is being developed as a specific thromboxane A-2 inhibitor. Non-steroidal anti-inflammatory agents such as ibuprofen are similar to aspirin in this regard except that the inhibition of COX-1 is reversible. Both aloxiprin and triflusal are aspirin-like products available in Europe that reversibly inhibit COX-1. Prostacyclin analogues, including iloprost, treprostinil, and cisaprost, vasodilate blood vessel surfaces as well as prevent platelet clumping, perhaps through the opposition of thromboxane.
ADP binding to the platelet surface is integral to platelet activation. The thienopyridines, including the approved agents ticlopidine, clopidogrel, and the experimental therapy prasugrel, block the ADP receptor, thereby preventing platelets from clumping. Similar to the thienopyridines, dipyridamole prevents the reuptake of ADP into platelets, thereby increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations, which impair platelet aggregation. The glycoprotein IIb/IIIa inhibitors such as abciximab, eptifibatide, tirofiban, prevent both platelet adhesion and platelet aggregation.
A series of agents known as procoagulants play an important role in the control of excessive bleeding. Many of these agents are commonly used in the surgical setting, although others have played an important role in the management of various hematologic disorders. Besides factor replacement therapies for hemophilia A and B, recombinant activated Factor VIIa has been used with considerable success in patients with inhibitors to Factors VIII and IX, as well as in patients with liver disease or Factor VII deficiencies or diffuse bleeding, especially after trauma.
Aminocaproic acid has also been used stabilize the fibrin clot by preventing plasminogen activation and, to a lesser degree, through promotion of antiplasmin activity. It is available as both an intravenous and an oral agent.
Apoprotein A (Apo A) attenuates tissue-plasminogen-activator-induced fibrinolysis and competitively interfere with plasminogen- and plasmin-induced pathways.
Another agent, 1-desamino-8-D-arginine-vasopression (DDAVP), stimulates the release of von Willebrand factor from endothelial stores and has also been used in Type I von Willebrand's disease as well as in select Type II cases, as it stimulates the release of von Willebrand's factor and Factor VIII from endothelial cells. It is also useful in enhancing platelet function in renal and liver failure. Its major limitations are that it can only be given three times over a day before the stores in the endothelial cells are exhausted and it can result in water intoxication.
Oral tranexamic acid, an inhibitor of fibrinolysis that blocks the lysine binding site of plasminogen to fibrin, has been shown to reduce the amount of post-operative blood loss following hip surgery compared with control, but is not available in the United States.
Topical thrombin and fibrin sealants can also help to stop local bleeding from lacerated tissues following trauma or surgery. Defibrotide, a porcine-derived, single-stranded piece of DNA, appears to reverse endothelial cell injury by increasing the level of prostaglandins, decreasing the release of thrombin, and increasing fibrinolysis. It is currently being tested in a phase III study for the treatment and prevention of post-stem cell transplant veno-occlusive disease.
Emerging anticoagulant therapies
The prodrug ximelegatran initially showed great promise as the first non-vitamin K oral direct thrombin inhibitor. However, due to concerns about hepatotoxicity, the U.S. Food and Drug Administration failed to approve this agent in 2004. Given the potential advantages of a direct oral thrombin inhibitor—including simpler and less frequent monitoring, less hospitalization and associated costs, no dietary restrictions, no need for heparinization, and greater patient convenience—research efforts have continued to focus on creating a less toxic alternative to ximelegatran.
A number of new oral anticoagulant agents, which could become much-needed replacements for warfarin and be used as alternatives to heparin, are under development. Two of these agents are now in phase III trials. Following the failure of ximelagatran, researchers are being quite cautious, although it is anticipated that some of these agents will soon be available. Two agents in particular appear to be farther along in clinical testing than the others, particularly dabigatran, a direct thrombin inhibitor, and rivaroxaban, a Factor Xa inhibitor. Both drugs are currently being tested in phase III studies.
The oral prodrug dabigatran etexilate, a direct thrombin inhibitor, has been studied in patients undergoing knee and hip replacement surgery and appears to be far less hepatotoxic than ximelegatran. The other agent currently in phase III testing is rivaroxaban. This oral direct factor Xa inhibitor has been studied in phase II trials for the treatment of VTE and phase III studies have been intiated for VTE prevention as well as stroke prevention in atrial fibrillation.
Other oral direct factor Xa inhibitors in clinical development include apixaban, YM150, DU-176b, LY517717, and PRT054021. The oral agent sulodexide, a glycoaminoglycan similar to heparin, is made up of 80% LMWH and 20% dermatan sulfate and functions as an anticoagulant through its effect on antithrombin and heparin cofactor II. Sulodexide is currently licensed for use in Europe and is also available as an injectable preparation, which would make it easy to begin use in the hospital and switch to an oral therapy upon discharge. Studies being conducted in this country are also looking at the effect of oral dermatan sulfate alone on thrombin inhibition via heparin cofactor II mediation.
Treatment advances in thrombocytopenia
Patients with immune-mediated thrombocytopenia (ITP) who failed to respond to a number of prior therapies, including steroids, immunoglobulin, anti-D treatment, rituximab, immunosuppressant agents, various cytotoxic chemotherapies, and splenectomy, represent a significant clinical challenge for their providers. One interesting approach to treating these patients is to recommend autologous stem cell transplantation. Investigators at the National Institutes of Health have transplanted 14 patients with refractory ITP. There were 6 complete responders, 2 partial responders, and 6 nonresponders, and follow-up times ranged from 9 to 42 months.
It has generally been assumed that in ITP, the peripheral destruction of platelets outstrips the bone marrow's ability to make new cells. In recent years, however, it has been hypothesized that platelet production in ITP is not entirely normal. Perhaps this is due to a defect in thrombopoietin or the receptor for thrombopoietin. Most treatment strategies for managing ITP have focused on the prevention of platelet destruction. If megakaryopoiesis could be upregulated, perhaps the balance could be tipped in favor of platelet production rather than destruction.
This hypothesis has led to the development of a number of hematopoietic stimulating agents that are showing great promise in the clinical setting. Thrombopoietin (TPO) is the major platelet growth factor responsible for stimulating platelet production. In early clinical studies, administration of TPO has been shown to upregulate platelet production. However, these agents triggered the development of autoantibodies against TPO that eventually decreased the production of native TPO, resulting in even lower platelet counts. Such therapies were ultimately abandoned.
More recently, investigators have developed thrombopoietic agents that have no structural similarity to TPO, although they have been shown to stimulate the TPO receptor, leading to increases in platelet production. Among these agents, AMG532, eltrombopag, and AKR-501 are further along in the process of clinical development. In particular, AMG531 has been shown to stimulate platelet production in normal subjects when administered subcutaneously. Currently, a phase III trial is studying the effects of AMG532 vs placebo in patients with ITP. Among 27 patients who completed 48 weeks of therapy, 86% had either doubled their platelet counts or increased their platelets to a target level of greater than 50,000/µL, while 81% of patients increased their platelet counts to greater than 150,000/µL at some point during therapy.
Eltrombopag, an oral thrombopoietin stimulating agent has shown a dose/response effect in phase I/II clinical studies and results from a phase III study have just been released, demonstrating that a once daily dose of 50 to 75 mg statistically increased the platelet count and reduced the incidence of bleeding in adults with ITP. After six weeks of therapy, 59% of patients given eltrombopag had platelet counts of greater than 50,000/µL, in comparison with 16% of patients on placebo. AKR-501 has also demonstrated activity in phase I studies of patients with ITP and a phase II trial is now ongoing.
Erythropoiesis-stimulating agents and thrombotic risk
Recently, the FDA issued an alert regarding information about the safety of the erythropoiesis-stimulating agents (ESAs) darbepoetin alfa and epoetin alfa, based on analysis from four studies in patients with cancer. The studies found that there was a higher mortality risk as well as an increased risk of serious side effects in those patients treated with ESAs. These data further heightened concerns about the risk of complications reported in two studies published in November 2006 among patients with renal failure who were receiving ESAs.
In the first of these studies, known as the CHOIR trial, patients with anemia and chronic kidney disease were randomized to receive epoetin alfa to maintain their hemoglobin levels at either 13.5 g/dL or 11.3 g/dL. The incidence of death and cardiovascular events was found to be statistically worse in the higher hemoglobin cohort. In the second study, known as the CREATE trial, the use of epoetin-β in a similar group of patients was associated with an increase in the risk of cardiovascular events.
Because all ESAs have the same mechanism of action, the FDA opined that the risks of treatment likely represented a class effect. Subsequently, the prescribing information for these agents has been changed and the new product labeling includes a boxed warning with recommended modifications in drug dose and administration. In summary, these changes recommend that clinicians use the lowest dose of ESAs to avoid prevent serious cardiovascular, arterial, and venous thromboembolic events.
Moreover, it cited study results indicating that use of ESAs to raise the hemoglobin level above 12 g/dL substantially increased the risk of death and serious cardiovascular events. For patients with head and neck cancer undergoing radiation therapy, time to tumor progression was shortened when ESAs were used to raise the hemoglobin above 12 g/dL. For patients with metastatic breast cancer undergoing chemotherapy, use of ESAs shortened overall survival and increased the incidence of dying. And for patients with active malignant disease not undergoing treatment with chemotherapy or radiation therapy, the FDA recommended avoidance of ESAs.
The new labeling also warned that patients treated with epoetin alfa prior to surgery to reduce the need for red blood cell transfusions had a higher incidence of deep venous thrombosis. Separate warnings were given for patients with uncontrolled hypertension and the labeling explicitly stated that ESAs do not alleviate fatigue or increase energy in patients with cancer.
The studies that precipitated these warnings included interim results published by the Danish Head and Neck Cancer Study Group trial (DANANCA 10), an open-label, randomized study comparing radiation alone with radiation plus darbepoetin alfa. The purpose of this trial was to determine whether maintaining the hemoglobin between 14 g/dL and 15.5 g/dL during radiotherapy would improve loco-regional control. In fact, the data safety monitoring committee for this study found that loco-regional control at three years was worse for patients whose hemoglobins were maintained at higher levels. And while not reaching statistical significance, overall survival was superior for the non-darbepoetin treatment cohort. These findings echoed results reported two years earlier by Henke regarding increased mortality and tumor progression in a similar patient cohort.
In a double-blind, multicenter, randomized, placebo-controlled study in cancer patients with anemia, darbepoetin alfa was given to raise the hemoglobin level to 12 g/dL, even though these patients were not receiving chemotherapy. As reported to the FDA in January 2007, the use of darbepoetin did not reduce the need for red cell transfusions, but did increase the incidence of mortality relative to the placebo group. In another study brought to the attention of the FDA in February 2007, anemic patients with non-small-cell lung cancer being treated with chemotherapy did not experience any quality of life improvements with the use of epoetin alfa when the hemoglobin level was maintained between 12 g/dL and 14 g/dL. In fact, the study was closed to further patient enrollment in December of 2003 after the data safety monitoring board found an increased number of deaths in the epoetin alfa treatment arm. In fact, the median time to death was 68 days in the epoetin alfa arm as opposed to 131 days in the placebo arm. Also in February of 2007, the FDA was notified by Hoffmann-LaRoche that a randomized study in patients with stage IIIB and IV non-small-cell lung cancer comparing a new pegylated epoetin-β product with darbepoetin alfa had been suspended because of safety concerns regarding increased mortality.
Finally, the FDA received information, also in February 2007, about preliminary results of a large, open-label, multicenter, randomized study comparing epoetin alfa with standard care in patients undergoing elective spinal surgery. Patients were given epoetin alfa to maintain their preoperative hemoglobin levels in the 10 g/dL to 13 g/dL range. The investigators reported that the incidence of venous thromboembolism (VTE) was 4.7%, more than twice the rate of those receiving supportive care alone.
These study results and subsequent FDA mandated warnings have raised real concerns about the current use of ESAs in cancer medicine. How these warnings will be interpreted by the oncology community that has been steeped in data regarding the benefits of such therapy for over a decade has yet to be determined.
Thrombosis and malignancy
The issue of cancer and venous thromboembolic disease is a significant one for both health care providers and their patients. Active cancer accounts for almost 20% of new VTEs and is particularly common in patients with lung, breast, colorectal, and prostate cancer, which represent the vast majorities of malignancies in this country. Patients diagnosed with cancer within a year of developing VTE have shorter life expectancies than patients who do not develop VTEs. This is likely due to the fact that the risk of bleeding is six times higher and the risk of recurrent VTE is two to three times higher in patients with cancer on warfarin therapy versus patients without cancer.
Treating VTEs in cancer patients is also quite different from the treatment of VTEs in patients without cancer. Low molecular weight heparin (LMWH) is preferred over unfractionated heparin for initial therapy because it can be given on an outpatient basis and is associated with a lower risk of HIT. In addition, recent data have shown that LMWH is more effective and safer than warfarin for prevention of recurrent VTE in patients with cancer. LMWH also obviates the need for laboratory monitoring, and provides a more constant level of anticoagulation than oral warfarin, particularly for patients with poor nutrition or gastrointestinal complications. However, the benefits of anticoagulation therapy must be balanced against the risks of bleeding, which for some cancer patients can be substantial.
Use of vena caval filters in cancer patients as an alternative to anticoagulation is also problematic. While vena caval filters may prevent pulmonary embolisms in the short term, they may increase the risk of recurrent DVTs and phlebitis.
Current recommendations for management and prevention of VTE in cancer patients include the following:
- Immobilized cancer patients who are hospitalized for medical reasons should receive VTE prophylaxis.
- There is currently no evidence to suggest that primary prophylaxis is both safe and effective in patients with cancer.
- Aromatase inhibitors have a lower risk of VTE than tamoxifen and should be used in postmenopausal women being treated for breast cancer.
- Patients with cancer who are undergoing elective surgery should receive LMWH prophylaxis while in hospital.
- The treatment of choice for cancer patients with VTE is LMWH.
- The optimal prevention of catheter-related thrombosis is unknown, and the optimal treatment of catheter-related thrombosis does not always require removal of the catheter.