University of Wisconsin Hematology

Coagulation: biology and clinical and laboratory evaluation

General

  1. Stefanucci et al. The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants. Blood 2023;142:2055 (Participants had a median of 7 pathogenic or likely pathogenic variants)
  2. Ross et al.Evaluating the clinical validity of genes related to hemostasis and thrombosis using the Clinical Genome Resource gene curation framework. J Thromb Haemost 2024;22:645
  3. Yong and Toh. Rethinking coagulation: from enzymatic cascade and cell-based reactions to a convergent model involving innate immune activation. Blood 2023;142:2133 (If you thought coagulation was complicated before, check this out)
  4. Zelaya et al. Nucleic acid sensing promotes inflammatory monocyte migration through biased coagulation factor VIIa signaling. Blood 2024;143:845 (More on the interplay of coagulation & inflammation)
  5. Megy et al. Curated disease‐causing genes for bleeding, thrombotic, and platelet disorders: Communication from the SSC of the ISTH. J Thromb Haemost 2019;17:1253
  6. Furie B. Pathogenesis of thrombosis. Hematology 2009;255
  7. Weisel and Litvinov Mechanisms of fibrin polymerization and clinical implications. Blood 2013;121:1712
  8. Luyendyk et al. The multifaceted role of fibrinogen in tissue injury and inflammation. Blood 2019;133:511
  9. Risman et al. Deconstructing fibrin(ogen) structure. J Thromb Haemost 2025;23:368
  10. Wagner and Frenette. The vessel wall and its interactions. Blood 2008;111:5271
  11. Swystun and Liaw. The role of leukocytes in thrombosis. Blood 2016;128:753
  12. Byrnes and Wolberg. Red blood cells in thrombosis. Blood 2017;130:1795
  13. Lassila and Weisel. Role of red blood cells in clinically relevant bleeding tendencies and complications. J Thromb Haemost 2023;22:3024
  14. Weisel and Litvinov. Red blood cells: the forgotten player in hemostasis and thrombosis. J Thromb Haemost 2019;17:271
  15. Borissoff et al. The hemostatic system as a modulator of atherosclerosis. NEJM 2011;364:1746
  16. Wolberg AS. Fibrinogen and fibrin: synthesis, structure, and function in health and disease. J Thromb Haemost 2023;21:3005
  17. Renné et al. In vivo roles of factor XII. Blood 2012;120:4296
  18. Ivanov et al. Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. Blood 2017;129:1527
  19. Long et al. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 2016;14:427
  20. Manon-Jensen et al. Collagen-mediated hemostasis. J Thromb Haemost 2016;14:438
  21. Attard et al. Developmental hemostasis: age-specific differences in the levels of hemostatic proteins. J Thromb Haemost 2013;11:1850
  22. Antoniak and Mackman. Multiple roles of the coagulation protease cascade during virus infection. Blood 2014;123:2605
  23. Griffin et al. Activated protein C: biased for translation. Blood 2015;125:2898 (Describes the cytoprotective role of APC and potential therapeutic benefit of engineered APC variants)
  24. Sinha et al. PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke. Blood 2018;131:1163
  25. Gu et al. Regulation of thrombosis and vascular function by protein methionine oxidation. Blood 2015;125:3851
  26. Nieman M. Protease-activated receptors in hemostasis. Blood 2016;128:169
  27. Posma et al. Coagulation and non-coagulation effects of thrombin. J Thromb Haemost 2016;14:1908
  28. Flaumenhaft and Furie. Vascular thiol isomerases. Blood 2016;128:893
  29. Fagerholm SC. Integrins in Health and Disease. NEJM 2022;387:1519

Thrombin generation

  1. Butenas et al. “Normal” thrombin generation. Blood 1999;94:2169
  2. Furie and Furie. Mechanisms of thrombus formation. NEJM 2008;359:938
  3. Harris et al. Coagulation tests: a primer for clinical chemists. Clin Lab News 2012:38
  4. Lane et al. Directing Thrombin.  Blood 2005;106:2605
  5. Colman and Schmaier. Contact system: a vascular biology mediator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997;90:3819
  6. Kravtsov et al. Factor XI contributes to thrombin generation in the absence of factor XII. Blood 2009;114:452
  7. Andrew et al. Maturation of the hemostatic system during childhood. Blood 1992;80:1998
  8. Attard et al. Developmental hemostasis: age-specific differences in the levels of hemostatic proteins. J Thromb Haemost 2013;11:1850
  9. Emsley et al. Structure and function of factor XI. Blood 2010;115:2569
  10. de Maat and Maas. Factor XII: form determines function. J Thromb Haemost 2016;14:1498
  11. Maas and Renné. Coagulation factor XII in thrombosis and inflammation. Blood 2018;131:1903

Platelets & von Willebrand factor

  1. Kaiser et al. Hemostasis without clot formation: how platelets guard the vasculature in inflammation, infection, and malignancy. Blood 2023;142:1413
  2. Izzi et al. Learning by counting blood platelets in population studies: survey and perspective a long way after Bizzozero. J Thromb Haemost 2018;16:1711 (Review of genetic and non-genetic determinants of the platelet count, health implications of variations in the count)
  3. Bye et al. Platelet signaling: a complex interplay between inhibitory and activatory networks. J Thromb Haemost 2016;14:918
  4. Shen et al. Coordination of platelet agonist signaling during the hemostatic response in vivo. Blood Adv 2017;1:2767 (Thromboxane and ADP signaling promotes platelet accumulation in the outer shell of the hemostatic plug; thrombin is the major activator in the core of the plug)
  5. Simon et al. Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics. Blood 2014;123:e37
  6. Beck et al. Temporal quantitative phosphoproteomics of ADP stimulation reveals novel central nodes in platelet activation and inhibition. Blood 2017;129:e1(With editorial)
  7. Schubert et al. A tour through the transcriptional landscape of platelets. Blood 2014;124:493
  8. Ho-Tin-Noé et al. Platelets and vascular integrity: how platelets prevent bleeding in inflammation. Blood 2018;131:277
  9. Gupta et al. Hemostasis vs. homeostasis: Platelets are essential for preserving vascular barrier function in the absence of injury or inflammation. PNAS 2020;117:24316
  10. Morrell et al. Emerging roles for platelets as immune and inflammatory cells. Blood 2014;123: 2759
  11. Randi and Laffan. Von Willebrand factor and angiogenesis: basic and applied issues. J Thromb Haemost 2017;15:13(Reviews evidence linking VWD and angiodysplasia)
  12. Wu et al. Platelets and von Willebrand factor in atherogenesis. Blood 2017;129:1415
  13. Grozovsky et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 2015;21:47(Aging platelets lose sialic acid, then bind to hepatic receptor that promotes TPO production)
  14. Jackson S. The growing complexity of platelet aggregation. Blood 2007;109:5087
  15. Edelstein et al. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med 2013;19:1609
  16. Mangin et al. Glycoprotein VI interplay with fibrin(ogen) in thrombosis. J Thromb Haemost 2023;21:1703 (Biology of the collagen receptor)
  17. Min and Abrans. Regulation of platelet plug formation by phosphoinositide metabolism. Blood 2013;122:1358
  18. Gawaz and Vogel. Platelets in tissue repair: control of apoptosis and interactions with regenerative cells. Blood 2013;122:2550
  19. Jackson and Schoenwaelder. Procoagulant platelets: are they necrotic? Blood 2010;116:2011
  20. McMorran et al. Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum. Science 2012;338:1348
  21. Nachman and Rafii. Platelets, Petechiae, and Preservation of the Vascular Wall. NEJM 2008;359:1261
  22. Shattil and Newman. Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood 2004;104:1606
  23. Springer TA. von Willebrand factor, Jedi knight of the bloodstream. Blood 104;124:1412
  24. Lenting et al. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015;125:2019
  25. Shim et al. Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 2008;111:651(Platelets enhance VWF cleavage by ADAMTS-13)
  26. Crawley et al. Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood 2011;118:3212
  27. Gilbert et al. Platelet binding sites for factor VIII in relation to fibrin and phosphatidylserine. Blood 2015;126:1237(Soluble fibrin enhances f VIII binding to platelets more effectively than PS; with editorial)
  28. Agbani et al. Coordinated Membrane Ballooning and Procoagulant Spreading in Human Platelets. Circulation 2015;132:1414(Supplementary material includes some interesting movies of platelets in action)
  29. Agbani and Poole. Procoagulant platelets: generation, function, and therapeutic targeting in thrombosis. Blood 2017;130:2171
  30. Coenen et al. Platelet interaction with activated endothelium: mechanistic insights from microfluidics. Blood 2017;130:2819
  31. Davizon-Castillo et al. TNF-α–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging. Blood 2019;134:727
  32. Nolte and Margadant. Activation and suppression of hematopoietic integrins in hemostasis and immunity. Blood 2020;135:7
  33. Atiq and O’Donnell. Novel functions for von Willebrand factor. Blood 2024;144:1247

Fibrinolysis; D-dimer

  1. Mutch and Medcalf.  The fibrinolysis renaissance. J Thromb Haemost 2023;21:3304
  2. Zheng et al. Assays to quantify fibrinolysis: strengths and limitations. Communication from the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee on fibrinolysis. J Thromb Haemost 2023;21:1043
  3. Keragala and Medcalf. Plasminogen: an enigmatic zymogen. Blood 2021;137:2881
  4. Longstaff C. Measuring fibrinolysis: from research to routine diagnostic assays. J Thromb Haemost 2018;16:652
  5. Williams EC. Plasma alpha 2-antiplasmin activity. Role in the evaluation and management of fibrinolytic states and other bleeding disorders. Arch Intern Med 1989;149:1769
  6. Favresse et al. D-dimer: Preanalytical, analytical, postanalytical variables, and clinical applications. Crit Rev Clin Lab Sci 2018;55:548
  7. Shapiro et al. Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency. Blood 2018;131:1301

Regulation of coagulation

  1. Mosnier et al. The cytoprotective protein C pathway. Blood 2007;109:3161
  2. Danese et al. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 2010;115:1121
  3. Cines et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998;91:3527
  4. Pluvinet et al. CD40: an upstream master switch for endothelial cell activation uncovered by RNAi-coupled transcriptional profiling. Blood 2008;112:3624
  5. Massberg et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010;16:887(Neutrophil proteases promote clotting by degrading TFPI)
  6. Morrissey et al. Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation. Blood 2012;119:5972
  7. Pozzi et al. β2-Glycoprotein I binds to thrombin and selectively inhibits the enzyme procoagulant functions. J Thromb Haemost 2013;11:1093
  8. Mast and Ruf. Regulation of coagulation by tissue factor pathway inhibitor: Implications for hemophilia therapy. J Thromb Haemost 2022;20:1290
  9. Wood et al. Biology of tissue factor pathway inhibitor. Blood 2014;123:2934
  10. Calzavarini et al. Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus. Blood 2020;135:1969

Diagnosis of bleeding disorders; screening tests

  1. Baker et al. Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH. J Thromb Haemost 2024;22:2059
  2. Simeoni et al. A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders. Blood 2016;127:2791(with editorial)
  3. Downes et al. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood 2019;134:2082(Molecular diagnosis found in 37% of patients)
  4. Downes et al. Clinical management, ethics and informed consent related to multi‐gene panel‐based high throughput sequencing testing for platelet disorders: Communication from the SSC of the ISTH. J Thromb Haemost 2020;18:2751
  5. Blombäck et al. Preanalytical conditions that affect coagulation testing, including hormonal status and therapy. J Thromb Haemost 2007;5:855
  6. Hayward C. Diagnosis and Management of Mild Bleeding Disorders. Hematology 2005:423-428
  7. Boender et al. A diagnostic approach to mild bleeding disorders. J Thromb Haemost 2016;14:1507
  8. Šrámek et al. Usefulness of patient interview in bleeding disorders. Arch Intern Med 1995;155:1409
  9. Eckman et al. Screening for the risk for bleeding or thrombosis. Ann Intern Med 2003;138:W-15(“For nonsurgical and surgical patients without synthetic liver dysfunction or a history of oral anticoagulant use, routine testing has no benefit in assessment of bleeding risk”)
  10. Ajdenberg et al. Sensitivity and specificity of strategies to identify patients with hemostasis abnormalities leading to an increased risk of bleeding before scheduled intervention: the Hemorisk study. J Thromb Haemost 2024;22:3048 (Bleeding questionnaire useful in women, not men; routine screening tests and more comprehensive test panel both less than 50% sensitive in predicting bleeding)
  11. O’Brien S. Evaluation and management of heavy menstrual bleeding in adolescents: the role of the hematologist. Blood 2018;132:2134
  12. Raza et al. The historical origins of modern international normalized ratio targets. J Thromb Haemost 2024;22:2184
  13. Le et al. The international normalized ratio (INR) for monitoring warfarin therapy: reliability and relation to other monitoring methods. Ann Intern Med 1994;120:552
  14. Hirsh and Poller. The international normalized ratio. A guide to understanding and correcting its problems. Arch Intern Med 1994;154:282
  15. Barton and Poon. Coagulation testing of Hickman catheter blood in patients with acute leukemia. Arch Intern Med 1986; 146:2165
  16. Michelson A.  Platelet function testing in cardiovascular disease.  Circulation 2004;110:e489
  17. Kolev and Longstaff. Bleeding related to disturbed fibrinolysis. Br J Haem 2016;175:12
  18. Thomas et al. The utility of viscoelastic methods in the prevention and treatment of bleeding and hospital‐associated venous thromboembolism in perioperative care: guidance from the SSC of the ISTH. J Thromb Haemost 2018;26:2336
  19. Nogami K. The utility of thromboelastography in inherited and acquired bleeding disorders. Br J Haem 2016;174:503
  20. Levi and Hunt. A critical appraisal of point-of-care coagulation testing in critically ill patients. J Thromb Haemost 2015;13:1960(TEG and ROTEM)
  21. Karkouti et al. Point-of-Care Hemostatic Testing in Cardiac Surgery A Stepped-Wedge Clustered Randomized Controlled Trial. Circulation 2016;134:1152(ROTEM testing reduced transfusion needs and bleeding after cardiac surgery)
  22. Dias et al. Thromboelastography‐guided therapy improves patient blood management and certain clinical outcomes in elective cardiac and liver surgery and emergency resuscitation: A systematic review and analysis. J Thromb Haemost 2019;17:984
  23. Amgalan et al. Systematic review of viscoelastic testing (TEG/ROTEM) in obstetrics and recommendations from the women’s SSC of the ISTH. J Thromb Haemost 2020;18:1813
  24. Lordkipanidzé et al. Characterization of multiple platelet activation pathways in patients with bleeding as a high-throughput screening option: use of 96-well Optimul assay. Blood 2014;123:e11
  25. Ver Donck et al.Strengths and limitations of high‐throughput sequencing for the diagnosis of inherited bleeding and platelet disorders. J Thromb Haemost 2020;18:1839
  26. Abrich et al. Risk factors for recurrent spontaneous epistaxis. Mayo Clin Proc 2014;89:1636
  27. Selak et al. Annual Risk of Major Bleeding Among Persons Without Cardiovascular Disease Not Receiving Antiplatelet Therapy. JAMA 2018; 319:2507