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 Jun Teruya
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Management
of Bleeding Patients
Second Edition

123
Management of Bleeding Patients
Jun Teruya
Editor

Management of Bleeding
Patients
Second Edition
Editor
Jun Teruya
Department of Pathology and Immunology
Division of Transfusion Medicine and Coagulation
Baylor College of Medicine, Texas Children’s Hospital
Houston, TX
USA

ISBN 978-3-030-56337-0    ISBN 978-3-030-56338-7 (eBook)

https://doi.org/10.1007/978-3-030-56338-7

© Springer Nature Switzerland AG 2021

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is
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Preface to the Second Edition

Since the first edition of this textbook was published in 2016, I am pleased by its success and
inspired by the community’s desire for a deeper understanding of the management of bleeding
patients demonstrated by the many purchases and downloads. I am happy to know that this text
was used by residents and fellows to enhance their hemostasis training. Our understanding of
the pathophysiology of hemostasis and improvements in management are continuously evolv-
ing. In order to provide the most updated knowledge and changes in practice, I decided to
publish the second edition. In the second edition, the following new chapters have been added:

• Hemostasis Basics: Figures and Facts

• Bleeding Due to Rare Coagulation Factor Deficiencies
• Bleeding Associated with Connective Tissue Disorders
• Massive Transfusion Protocol
• Management of Bleeding Associated with Durable Mechanical Circulatory Support
• Evaluation of Bleeding Risk Prior to Pediatric Invasive Procedures
• Evaluation of Bleeding Risk Prior to Invasive Procedures in Adults

I thank all the dedicated authors who contributed to this second edition.
I am hoping this edition will be more useful than the first for the management of bleeding
patients.

Houston, TX, USA Jun Teruya

v
Contents

Part I Diagnosis of Bleeding by Laboratory Testing

1 Hemostasis Basics: Figures and Facts�����������������������������������������������������������������������   3

Jun Teruya
2 Screening Coagulation Assays, Factor XIII and D-dimer��������������������������������������� 11
Dorothy M. Adcock and Brian F. Poirier
3 Platelets ����������������������������������������������������������������������������������������������������������������������� 25
Kandice Kottke-Marchant
4 Von Willebrand Disease Laboratory Workup ��������������������������������������������������������� 33
Shiu-Ki Rocky Hui
5 Hyperfibrinolysis��������������������������������������������������������������������������������������������������������� 39
Wayne L. Chandler
6 Whole Blood Assay: Thromboelastometry – Basics������������������������������������������������� 45
Klaus Görlinger, James Iqbal, Daniel Dirkmann, and Kenichi A. Tanaka
7 Whole Blood Assay: Thromboelastometry – Bleeding
Management Algorithms ������������������������������������������������������������������������������������������� 67
Klaus Görlinger, James Iqbal, Daniel Dirkmann, and Kenichi A. Tanaka

Part II Bleeding Associated with Disease Condition

8 Known Bleeding Disorders for Surgery������������������������������������������������������������������� 91

Miguel A. Escobar, Trinh Nguyen, and Natalie A. Montanez
9 Hemophilia A, Hemophilia B, Congenital von Willebrand
Disease, and Acquired von Willebrand Syndrome��������������������������������������������������� 103
Shiu-Ki Rocky Hui
10 Bleeding Associated with Coagulation Factor Inhibitors��������������������������������������� 113
Charles Eby
11 Bleeding Due to Rare Coagulation Factor Deficiencies������������������������������������������� 121
Nicola Curry
12 Pregnancy-Associated Bleeding��������������������������������������������������������������������������������� 131
Karin A. Fox
13 Bleeding Associated with Thrombocytopenia����������������������������������������������������������� 141
Sarah E. Sartain and Jenny Despotovic
14 Bleeding in Acute and Chronic Liver Disease ��������������������������������������������������������� 157
Price T. Edwards, Tamir Miloh, Esther P. Soundar, and Jun Teruya

vii
viii Contents

15 Bleeding and Hyperfibrinolysis��������������������������������������������������������������������������������� 165

Wayne L. Chandler
16 Bleeding of Unknown Etiology ��������������������������������������������������������������������������������� 173
Jun Teruya, Lisa Hensch, and Vadim Kostousov
17 Bleeding Associated with Disseminated
Intravascular Coagulation����������������������������������������������������������������������������������������� 181
Charles Eby
18 Bleeding and Vitamin K Deficiency��������������������������������������������������������������������������� 187
Charles Eby
19 Bleeding in Uremia����������������������������������������������������������������������������������������������������� 193
Jens Lutz and Julia Weinmann-Menke
20 Bleeding Associated with Connective Tissue Disorders������������������������������������������� 201
Dominder Kaur and Bryce A. Kerlin
21 Bleeding Associated with Trauma����������������������������������������������������������������������������� 211
Christoph J. Schlimp and Martin Ponschab
22 Massive Transfusion Protocol ����������������������������������������������������������������������������������� 215
Megan E. Cunningham and Adam M. Vogel
23 Lupus Anticoagulant-­Hypoprothrombinemia
Syndrome (LAHPS) ��������������������������������������������������������������������������������������������������� 219
Mona D. Shah

Part III Bleeding from Specific Organs

24 Intracerebral Hemorrhage: An Overview of Etiology,

Pathophysiology, Clinical Presentation, and Advanced
Treatment Strategies��������������������������������������������������������������������������������������������������� 227
Burhan Z. Chaudhry and Edward M. Manno
25 Epistaxis����������������������������������������������������������������������������������������������������������������������� 239
Elton Lambert and Ellen M. Friedman
26 Bleeding Disorders Related to Lung Disease����������������������������������������������������������� 247
David R. Spielberg, Timothy J. Vece, and George B. Mallory Jr.
27 Heavy Menstrual Bleeding����������������������������������������������������������������������������������������� 255
Lakshmi V. Srivaths, Jennifer L. Bercaw-Pratt, Oluyemisi Adeyemi-Fowode,
and Jennifer E. Dietrich
28 Gross Hematuria��������������������������������������������������������������������������������������������������������� 267
Monica Velasquez and Adam S. Feldman
29 Upper Gastrointestinal Bleeding������������������������������������������������������������������������������� 275
Nabeel Azeem and Martin L. Freeman

Part IV Bleeding Associated with Medication

30 Antiplatelet and Anticoagulant Agents��������������������������������������������������������������������� 289

Ibrahim F. Ibrahim and Lawrence Rice
31 Thrombolytic Therapy: tPA-Induced Bleeding������������������������������������������������������� 303
Jennifer Erklauer
Contents ix

Part V Bleeding Associated with Procedure

32 Bleeding Associated with ECMO������������������������������������������������������������������������������� 313

Jun Teruya and Cole Burgman
33 Management of Bleeding Associated with Durable
Mechanical Circulatory Support������������������������������������������������������������������������������� 321
Peter Collins, Katelyn W. Sylvester, and Jean M. Connors
34 Bleeding Related to Cardiac Surgery����������������������������������������������������������������������� 329
Hlaing Tint, Brian Castillo, Paul Allison, and Alice J. Chen
35 Bleeding Related to Liver Transplant����������������������������������������������������������������������� 339
Klaus Görlinger, Tetsuro Sakai, Daniel Dirkmann, Raymond M. Planinsic,
Khaled Yassen, and Fuat H. Saner
36 Percutaneous Image-Guided Interventions Including
Solid Organ Biopsies��������������������������������������������������������������������������������������������������� 361
Shiraz Rahim, Indravadan J. Patel, and Jon Davidson
37 Dental Extractions in Patients with Congenital and
Acquired Bleeding Disorders������������������������������������������������������������������������������������� 377
Julia A. M. Anderson and Andrew Brewer

Part VI Specific Issues in Neonates and Pediatrics

38 Neonatal Thrombocytopenia������������������������������������������������������������������������������������� 387

Rebecca Barton and Paul Monagle
39 Bleeding in the Neonate ��������������������������������������������������������������������������������������������� 395
Sally Campbell and Paul Monagle

Part VII Evaluation of Bleeding Risk Prior to Invasive Procedures

40 Evaluation of Bleeding Risk Prior to Pediatric

Invasive Procedures ��������������������������������������������������������������������������������������������������� 403
Lisa Hensch
41 Evaluation of Bleeding Risk Prior to Invasive Procedures������������������������������������� 411
Andrea Lewin, Katelyn W. Sylvester, and Jean M. Connors

Part VIII Hemostatic Agents and Blood Components

Used to Stop Bleeding

42 Hemostatic Agents and Blood Components

Used to Stop Bleeding������������������������������������������������������������������������������������������������� 425
Brady S. Moffett and Rachel S. Carroll
43 Blood Components ����������������������������������������������������������������������������������������������������� 445
Lisa Hensch

Index������������������������������������������������������������������������������������������������������������������������������������� 463
Contributors

Dorothy M. Adcock, MD LabCorp Diagnostics, Burlington, NC, USA

Oluyemisi Adeyemi-Fowode, MD Division of Pediatrics and Gynecology, Department of
Obstetrics and Gynecology, Texas Children’s Hospital, Houston, TX, USA
Paul Allison, MD Department of Pathology, Memorial Hermann-Texas Medical Center,
Houston, TX, USA
Julia A. M. Anderson, MBChB BSc MD FRCP Edin FRCPath Department of Haematology,
Royal Infirmary of Edinburgh, Edinburgh, UK
Nabeel Azeem, MD Division of Gastroenterology, Hepatology and Nutrition, Department of
Medicine, University of Minnesota Medical Center, Minneapolis, MN, USA
Rebecca Barton, MBBS, BBioMedSci Department of Clinical Haematology, Royal
Children’s Hospital, Parkville, VIC, Australia
Jennifer L. Bercaw-Pratt, MD Department of Obstetrics and Gynecology, Baylor College of
Medicine, Houston, TX, USA
Andrew Brewer, BSc, BChD, MFDS RCPS(Glasg) Regional Maxillofacial Unit, Queen
Elizabeth University Hospital, Glasgow, UK
Cole Burgman, BS ECMO Department, Texas Children’s Hospital, Houston, TX, USA
Sally Campbell, BSc, MBBS Hons, FRACP, FRCPA Department of Clinical Haematology,
Royal Children’s Hospital, Parkville, VIC, Australia
Rachel S. Carroll, PharmD Pediatric Hematology, Department of Pharmacy, Texas
Children’s Hospital, Houston, TX, USA
Brian Castillo, MD Department of Pathology and Genomic Medicine, Houston Methodist
Hospital, Houston, TX, USA
Wayne L. Chandler, MD Laboratory Medicine, Seattle Children’s Hospital, Seattle, WA,
USA
Burhan Z. Chaudhry, MD Department of Neurology, University of Missouri, Columbia,
MO, USA
Alice J. Chen, MD, PhD Department of Pathology, HCA Houston Healthcare Medical
Center, Houston, TX, USA
Peter Collins, PharmD, CACP Department of Pharmacy, Brigham and Women’s Hospital,
Boston, MA, USA
Jean M. Connors, MD Hemostatic and Antithrombotic Stewardship, Brigham and Women’s
Hospital, Boston, MA, USA
Division of Hematology, Department of Medicine, Harvard Medical School, Boston, MA,
USA

xi
xii Contributors

Megan E. Cunningham, MD Department of Pediatric Surgery, Texas Children’s Hospital/

Baylor College of Medicine, Houston, TX, USA
Nicola Curry, MD, MBBChir, FRCP, FRCPath Department of Haematology, Oxford
Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK
Jon Davidson, MD, FSIR Department of Interventional Radiology, University Hospitals
Cleveland Medical Center, Cleveland, OH, USA
Jenny Despotovic, DO, MS Department of Pediatrics, Section of Hematology/Oncology,
Baylor College of Medicine, Houston, TX, USA
Jennifer E. Dietrich, MD, MSc Obstetrics and Gynecology and Pediatrics, Baylor College
of Medicine, Texas Children’s Hospital, Houston, TX, USA
Daniel Dirkmann, MD, PhD Department of Anesthesiology and Intensive Care Medicine,
University Hospital Essen, Essen, Germany
Charles Eby, MD Division of Laboratory and Genomic Medicine, Department of Pathology
and Immunology, Washington University School of Medicine, St. Louis, MO, USA
Price T. Edwards, MD Department of Pediatrics, Section of Gastroenterology, Hepatology,
and Nutrition, Texas Children’s Hospital, Houston, TX, USA
Jennifer Erklauer, MD Sections of Critical Care Medicine and Child Neurology and
Developmental Neurosciences, Department of Pediatrics, Texas Children’s Hospital, Baylor
College of Medicine, Houston, TX, USA
Miguel A. Escobar, MD Department of Internal Medicine, University of Texas Health
Science Center and the McGovern Medical School, Houston, TX, USA
Gulf States Hemophilia & Thrombophilia Center, University of Texas Health Science Center,
Houston, TX, USA
Department of Pediatrics, Division of Hematology, University of Texas Health Science Center
and the McGovern Medical School, Houston, TX, USA
Adam S. Feldman, MD, MPH Department of Urology, Massachusetts General Hospital/
Harvard Medical School, Boston, MA, USA
Karin A. Fox, MD, MEd Department of Obstetrics and Gynecology, Baylor College of
Medicine/Texas Children’s Hospital, Houston, TX, USA
Martin L. Freeman, MD Division of Gastroenterology, Hepatology and Nutrition,
Department of Medicine, University of Minnesota Medical Center, Minneapolis, MN, USA
Ellen M. Friedman, MD Department of Otolaryngology, Texas Children’s Hospital, Houston,
TX, USA
Klaus Görlinger, MD Department of Anesthesiology and Intensive Care Medicine, University
Hospital Essen, Essen, Germany
Tem Innovations GmbH, Munich, Germany
Lisa Hensch, MD Department of Pathology and Immunology, Division of Transfusion
Medicine and Coagulation, Baylor College of Medicine, Texas Children’s Hospital, Houston,
TX, USA
Shiu-Ki Rocky Hui, MD Department of Pathology and Immunology, Division of Transfusion
Medicine and Coagulation, Baylor College of Medicine, Texas Children’s Hospital, Houston,
TX, USA
Contributors xiii

Ibrahim F. Ibrahim, MD Department of Internal Medicine, Division of Hematology and

Oncology, University of Texas Southwestern, Dallas, TX, USA
James Iqbal, MD, PhD Department of Pathology and Laboratory Medicine, James J. Peters
VA Medical Center, Bronx, NY, USA
Dominder Kaur, MD, MSc Department of Pediatrics, Division of Pediatric Oncology,
Hematology, and SCT, Columbia University Irving Medical Center (CUIMC)/Children’s
Hospital of New York, New York, NY, USA
Bryce A. Kerlin, MD Department of Pediatrics, The Ohio State University College of
Medicine, Nationwide Children’s Hospital, Columbus, OH, USA
Vadim Kostousov, MD Department of Pathology and Immunology, Division of Transfusion
Medicine and Coagulation, Baylor College of Medicine, Texas Children’s Hospital, Houston,
TX, USA
Kandice Kottke-Marchant, MD, PhD Department of Laboratory Medicine, Cleveland
Clinic, Cleveland, OH, USA
Elton Lambert, MD Department of Otolaryngology, Baylor College of Medicine, Texas
Children’s Hospital, Houston, TX, USA
Andrea Lewin, PharmD, CACP Department of Pharmacy, Brigham and Women’s Hospital,
Boston, MA, USA
Jens Lutz, MD Department of Internal Medicine Nephrology-Infectious Diseases, Central
Rhine Hospital Group, Klinikum Kemperhof, Academic Teaching Hospital University
Medicine Mainz, Koblenz, Germany
George B. Mallory Jr., MD Department of Pediatrics, Section of Pulmonary Medicine,
Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA
Edward M. Manno, MD FANA, FAAN, FAHA, FCCM, FNCS Department of Neurology,
Northwestern Memorial Hospital/Northwestern Feinberg School of Medicine, Chicago, IL,
USA
Tamir Miloh, MD Department of Gastroenterology, Baylor College of Medicine, Houston,
TX, USA
Brady S. Moffett, PharmD, MPH Department of Pharmacy, Texas Children’s Hospital –
The Woodlands, The Woodlands, TX, USA
Paul Monagle, MBBS, MSc, MD Department of Clinical Haematology, Royal Children’s
Hospital, Parkville, VIC, Australia
Natalie A. Montanez, MSN, FNP-C Gulf States Hemophilia & Thrombophilia Center,
University of Texas Health Science Center, Houston, TX, USA
Department of Pediatrics, Division of Hematology, University of Texas Health Science Center
and the McGovern Medical School, Houston, TX, USA
Trinh Nguyen, DO Department of Hematology-Oncology, The University of Texas-Health
Science Center-Houston, MD Anderson Children’s Cancer Center, Houston, TX, USA
Gulf States Hemophilia and Thrombophilia Treatment Center, Houston, TX, USA
Indravadan J. Patel, MD Department of Radiology, University Hospitals Cleveland Medical
Center, Cleveland, OH, USA
xiv Contributors

Raymond M. Planinsic, MD Department of Anesthesiology and Perioperative Medicine,

University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Brian F. Poirier, MD Colorado Coagulation, Laboratory Corporation of America® Holdings,
Englewood, CO, USA
Martin Ponschab, MD, PD AUVA Research Center, Ludwig Boltzmann for Experimental
and Clinical Traumatology, Vienna, Austria
Shiraz Rahim, MD Department of Interventional Radiology, Rush University Medical
Center, Chicago, IL, USA
Lawrence Rice, MD Department of Medicine, Weill Cornell Medical College (Houston
Campus), Houston, TX, USA
Department of Medicine and Cancer Center, Houston Methodist Hospital, Houston, TX, USA
Tetsuro Sakai, MD, PhD, MHA, FASA Department of Anesthesiology and Perioperative
Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Fuat H. Saner, MD, PhD Department of General, Visceral, and Transplant Surgery, Medical
Center University Duisburg-Essen, Essen, Germany
Sarah E. Sartain, MD Department of Pediatrics, Section of Hematology-Oncology, Texas
Children’s Cancer and Hematology Centers, Houston, TX, USA
Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA
Christoph J. Schlimp, MD, PD AUVA Research Center, Ludwig Boltzmann for Experimental
and Clinical Traumatology, Vienna, Austria
Mona D. Shah, MD, MS, MBA Genentech, Inc. (Roche), Product Development - Hematology
(PDH), Rare Blood Disorders (RBD), South San Francisco, CA, USA
Esther P. Soundar, MD, MPH Department of Pathology and Laboratory Medicine, Indiana
University School of Medicine, Indianapolis, IN, USA
David R. Spielberg, MD, MHSc Department of Pediatrics, Section of Pulmonary Medicine,
Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA
Lakshmi V. Srivaths, MD Department of Pediatrics, Section of Hematology, Young Women’s
Bleeding Disorder Clinic, Baylor College of Medicine/Texas Children’s Hospital, Houston,
TX, USA
Katelyn W. Sylvester, PharmD, CACP Department of Pharmacy, Brigham and Women’s
Hospital, Boston, MA, USA
Kenichi A. Tanaka, MD, PhD Department of Anesthesiology, Division of Cardiothoracic
Anesthesiology, University of Maryland Medical Center, Baltimore, MD, USA
Jun Teruya, MD, DSc, FCAP Department of Pathology and Immunology, Division of
Transfusion Medicine and Coagulation, Baylor College of Medicine, Texas Children’s
Hospital, Houston, TX, USA
Hlaing Tint, MD Department of Pathology and Laboratory Medicine, McGovern Medical
School, Houston, TX, USA
Memorial Hermann Hospital-Texas Medical Center, Houston, TX, USA
Timothy J. Vece, MD Department of Pediatrics, University of North Carolina School of
Medicine, Chapel Hill, NC, USA
Contributors xv

Monica Velasquez, MD Department of Pediatric Surgery, Advocate Children’s Hospital, Oak

Lawn, IL, USA
Adam M. Vogel, MD Department of Pediatric Surgery, Texas Children’s Hospital/Baylor
College of Medicine, Houston, TX, USA
Julia Weinmann-Menke, MD Department of Medicine, Division of Nephrology, Medical
Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Khaled Yassen, MSc, MD, FFARCSI Department of Anaesthesia and Intensive Care,
National Liver Institute, Menoufia University, Shebeen El-Kom, Menoufia Governorate, Egypt
Department of Surgery, College of Medicine, King Faisal University, Al-Ahsa Governorate, Al
Hofuf, Saudi Arabia
About the Editor

Jun Teruya, MD, DSc is tenured Professor and Vice Chairman

for Education in the Department of Pathology and Immunology,
with secondary appointments as tenured Professor in the
Departments of Pediatrics and Medicine at Baylor College of
Medicine, Houston, USA. He is Chief of the Division of
Transfusion Medicine and Coagulation at Texas Children’s
Hospital.
Professor Teruya received his MD and Doctor of Science
(DSc) degrees from Japan. After practicing Internal Medicine
and Hematology for 10 years in Japan, he went to Massachusetts
General Hospital (MGH), Harvard Medical School, for resi-
dency training in Clinical Pathology and Blood Bank fellow-
ship. He became an Acting Assistant Director of the Blood
Transfusion Service at MGH when he was a second year resi-
dent and Assistant Director the next year while he was a Blood
Banking/Transfusion Medicine fellow. Since moving to his
current institution in 2001, he has been engaged in managing
patients with active and/or massive bleeding.
Professor Teruya has received numerous teaching awards,
including Best Clinical Teacher of Clinical Pathology at MGH,
Pediatric Award for Excellence in Teaching, Best Educator in
Clinical Pathology (twice), and the Funniest Professor Award
at Baylor College of Medicine. He was also selected as a Top
Doctor in Transfusion Medicine and Coagulation by Houstonia
Magazine in 2013 and Best Doctor in America since 2015.
Professor Teruya serves as the Chairman of the Plasma
Coagulation Inhibitors subcommittee of the International
Society of Thrombosis and Hemostasis. He also organized an
International ECMO/VAD Interest group in 2017 that has 40
members worldwide. He has authored about 150 journal arti-
cles and 25 book chapters both including pending acceptance
or manuscripts in preparation.

xvii
 Part I
Diagnosis of Bleeding by Laboratory Testing
 Hemostasis Basics: Figures and Facts
1
Jun Teruya

Introduction

In order to understand hemostatic system easily, visualiza-

tion is usually more effective than text. While the details of
each system are found in other chapters of this textbook,
Figs. 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9 give a gen-
eral overview of the hemostatic system. Explanations for
each figure are included in the legend. The tables list charac-
teristics of individual coagulation factors and von Willebrand
factor. The half-life of each factor, minimum requirement for
hemostasis, and choice of blood components or hemostatic
drugs may be clinically useful (Figs. 1.1, 1.2, 1.3, 1.4, 1.5,
1.6, 1.7, 1.8, and 1.9; Tables 1.1, 1.2, and 1.3).

Acknowledgment I am grateful to Lisa Hensch, MD for her review of

this chapter.

J. Teruya (*)
Department of Pathology and Immunology,
Division of Transfusion Medicine and Coagulation,
Baylor College of Medicine, Texas Children’s Hospital,
Houston, TX, USA
e-mail: jxteruya@txch.org

© Springer Nature Switzerland AG 2021 3

J. Teruya (ed.), Management of Bleeding Patients, https://doi.org/10.1007/978-3-030-56338-7_1
4 J. Teruya

Fig. 1.1 When there is a defective vessel wall, von Willebrand factor
(VWF) binds to the subendothelial matrix (composed of collagen) via
the A1 and A3 domains of VWF under shear force. Platelets bind to the
A1 domain of VWF via glycoprotein Ib. Platelets bound to the suben-
dothelial matrix are activated. These activated platelets undergo shape
change and degranulation, resulting in further platelet activation and
the formation of platelet aggregates. This process is called primary
hemostasis or platelet hemostasis. The coagulation cascade is activated
by negatively charged surface and tissue factor and ultimately results in
the formation of fibrin which is crosslinked via factor XIIIa. Together,
crosslinked fibrin and platelet aggregates form a strong clot. This pro-
cess is known as secondary hemostasis or coagulation hemostasis.
Finally, once the defective vessel wall is healed, the clot is removed by
the action of plasmin in a process called fibrinolysis. GPIa glycoprotein
Ia, GPIb glycoprotein Ib, TXA2 thromboxane A2. © 2019, Texas
Children’s Hospital. Reproduced/used with permission
1 Hemostasis Basics: Figures and Facts
Fig. 1.2 The coagulation process was initially called “waterfall
sequence for intrinsic blood clotting” in order to explain fibrin clot for-
mation (Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood
clotting. Science. 1964;145:1310–12.). Then, it was called “coagulation
cascade.” Now it is known that coagulation is not a one-way process.
Thrombin provides positive feedback to activate various coagulation
factors. See Fig. 1.3. © 2019, Texas Children’s Hospital. Reproduced/
used with permission
Fig. 1.3 When a vessel is injured, the factor VIIa (a small amount of
activated form is circulating) and tissue factor complex activates factor
IX and factor X to factor IXa and factor Xa, respectively. Tissue factor
pathway inhibitor (TFPI) inhibits the activation of factor IX and factor
X. Factor Xa together with factor Va, called prothrombinase, activates
prothrombin to thrombin. Thrombin activates factor XI, factor VIII, fac-
tor V, and factor XIII and converts fibrinogen to fibrin. Thrombin also
forms a complex with thrombomodulin on the endothelial cells. This
5
Fig. 1.4 The interaction of thrombin with fibrinogen results in the
release of fibrinopeptide A (FPA) and fibrinopeptide B (FPB). A fibrin
monomer is formed after releasing FPA and FPB. The fibrin monomers
polymerize spontaneously. Thrombin also activates factor XIII to factor
XIIIa, which crosslinks fibrin. Eventually, crosslinked fibrin will be
degraded to D-dimer by plasmin. © 2019, Texas Children’s Hospital.
Reproduced/used with permission
complex then activates protein C to activated protein C and thrombin-­
activatable fibrinolysis inhibitor (TAFI) to TAFIa. Thrombin continues
activating these factors until the process is completely inhibited by anti-
thrombin and activated protein C. Of note, thrombin formation occurs
without involvement of factor XII, which is why hemostasis is main-
tained in patients with factor XII deficiency. However, when factor XII
is activated to factor XIIa, thrombin is formed. © 2019, Texas Children’s
Hospital. Reproduced/used with permission
6 J. Teruya

Fig. 1.5 Plasminogen is

converted to plasmin by the
actions of tissue plasminogen
activator (tPA) and urokinase-
type plasminogen activator
(uPA). Plasmin cleaves
fibrinogen, fibrin, fibronectin,
thrombospondin, laminin, and
von Willebrand factor.
Plasmin is inactivated by
α2-antiplasmin and α2-­
macroglobulin. Plasminogen
activator inhibitor 1 (PAI-1)
and histidine-rich
glycoprotein inhibit the
actions of tPA and uPA. ©
2019, Texas Children’s
Hospital. Reproduced/used
with permission

Virchow’s Triad in Thrombosis

a
Fig. 1.6 Virchow proposed three key elements in the development of
thrombosis (a). Hypofibrinolysis may be added to the triad (b). PAI-1
plasminogen activator inhibitor 1. © 2019, Texas Children’s Hospital.
Reproduced/used with permission

b Quad in Thrombosis
1 Hemostasis Basics: Figures and Facts
Fig. 1.7 Without heparin or heparinoids, antithrombin (AT) slowly
inhibits factor Xa and thrombin. This is the “progressive form” of
AT. AT also inhibits factor VIIa, factor IXa, and, to lesser extent,
factor XIa. Unfractionated heparin (UFH) or low-molecular-weight
heparin (LMWH) forms a complex with AT resulting in a confirma-
tional change in AT and accelerating its anticoagulant action. This
is called the “immediate form” of AT. The AT and UFH complex
7
inhibits thrombin and factor Xa immediately. Alternatively, the AT
and LMWH complex inhibits primarily factor Xa immediately.
Heparin also binds heparin cofactor II which inhibits only throm-
bin. Heparin additionally functions as an anticoagulant by causing
the release of tissue factor pathway inhibitor (TFPI) from endothe-
lial cells. © 2019, Texas Children’s Hospital. Reproduced/used
with permission
8 J. Teruya

Fig. 1.8 Protein C binds to the endothelial protein C receptor (EPCR),
and thrombin makes a complex with thrombomodulin (TM) on the
endothelial cell surface. The thrombin thrombomodulin complex acti-
vates protein C which is bound to EPCR. Activated protein C (aPC)
makes a complex with free protein S and inactivates factor Va. The aPC
and protein S complex binds to factor V and inactivates factor VIIIa.
This pathway inhibits procoagulant activity resulting in the prevention
of excessive clot formation. C4bBP C4b binding protein, PS protein S,
FV factor V, FVa activated factor V, FVi inactivated factor V, FVIII fac-
tor VIII, FVIIIa activated factor VIII, FVIIIi inactivated factor VIII,
APC activated protein C, PC protein C. © 2019, Texas Children’s
Hospital. Reproduced/used with permission

Fig. 1.9 In a normal state,

procoagulants and
anticoagulants are well
balanced. AT antithrombin,
PC protein C, PS protein S,
TFPI tissue factor pathway
inhibitor, α2M α2-­
macroglobulin. © 2019, Texas
Children’s Hospital.
Reproduced/used with
permission
1 Hemostasis Basics: Figures and Facts 9

Table 1.1 Characteristics of coagulation factors, contact factors, and von Willebrand factor
Molecular weight (Daltons) Concentration in 1 mL Concentration required for normal
Factor Common name (activated form) plasma hemostasis
I Fibrinogen 340,000 3 mg 100 mg/dL
(330,000)
II Prothrombin 72,000 100 μg 20–40%
(38,000)
III Tissue factor 45,000 0.02 μg
IV Calcium ions
V Proaccelerin 330,000 10 μg >25%
VII Proconvertin 50,000 0.5 μg 10–20%
(50,000)
VIII Antihemophilic factor 280,000 0.1 μg Minimum of 30% for major
surgery; less for minor
procedures
IX Christmas factor 56,000 3–4 μg 25–30%
(46,000)
X Stuart factor 55,000 6–8 μg 10–20%
(40,000)
XI Plasma thromboplastin 160,000 7 μg 15–25%
antecedent (160,000)
XII Hageman factor 80,000 30 μg None required
(80,000)
XIII Fibrin stabilizing factor 320,000 60 μg >5%
(320,000)
von Willebrand factor 1.2–5 million 7 μg 50%
Prekallikrein 100,000 35–45 μg None required
High-molecular-weight 120,000 80 μg None required
kininogen

Table 1.2 Characteristics of coagulation factors and von Willebrand factor

Factor In vivo half-life Storage characteristics Choice of components or hemostatic drug for replacement
Ia 3–5 days Stable in plasma at 4 °C Cryoprecipitate, fibrinogen concentrate (RiaSTAP™,
Fibryga™)
II 2–3 days Stable in plasma at 4 °C FFP, prothrombin complex concentrate (Kcentra™)
V 12 hours Labile except when frozen FFP
VII 3–6 hours Stable in plasma at 4 °C Recombinant activated factor VII (NovoSeven™), FFP,
prothrombin complex concentrate (Kcentra™)
VIIIa 8–12 hours Labile except when frozen Factor VIII concentrate, recombinant factor VIII
IX 18–24 hours Stable in plasma at 4 °C Factor IX concentrate, recombinant factor IX
X 30–40 hours Stable in plasma at 4 °C Prothrombin complex concentrate (Kcentra™, Coagadex™)
XI 52 hours Stable in plasma at 4 °C FFP, factor XI concentrate (not available in US)
XII 60 hours Stable in plasma at 4 °C Not necessary
XIII 9–10 days Stable in plasma Cryoprecipitate, factor XIII concentrate, recombinant factor
XIII
VWFa 9–15 hours Labile except when frozen Humate-P™, Wilate™, Alphanate™, Vonvendi™
Cryoprecipitateb
FFP fresh frozen plasma, VWF von Willebrand factor
a
Acute phase reactant
b
If VWF concentrate or recombinant VWF is not available
10 J. Teruya

Table 1.3 Natural anticoagulants

Activation/mechanism
of action Inhibiting factors
Antithrombin To immediate form Thrombin, factor Xa
by heparin and
heparan sulfate
Protein C Thrombin-­ Factor Va, factor
thrombomodulin VIIIa
complex
Protein S Cofactor of activated Factor Va, factor
protein C VIIIa
Tissue factor Factor Xa, tissue
pathway inhibitor factor, and factor
(TFPI) VIIa complex
Heparin cofactor II To immediate form Thrombin
by heparin and
dermatan sulfate
α2-macroglobulin Thrombin, factor Xa
 Screening Coagulation Assays,
Factor XIII and D-dimer
Dorothy M. Adcock and Brian F. Poirier
Physiologic Hemostasis
Hemostasis is the physiologic means by which the body both
maintains circulatory flow and stops the loss of blood [1]. It
is an intricate and complex process that relies on the interac-
tion of multiple cellular components and protein pathways
that serves to both maintain blood in a fluid state yet func-
tions to develop a physical barrier to prevent excessive bleed-
ing from injured blood vessels when needed. The system is
highly regulated through a number of different mechanisms,
in part being composed of proenzymes, procoagulant pro-
teins, and anticoagulant proteins. Clot formation initiates the
fibrinolytic system that functions to limit clot size and in
some circumstances results in clot dissolution. The fibrino-
lytic system is also highly regulated containing proenzymes
as well as profibrinolytic and antifibrinolytic proteins.
Disorders in either clot formation or fibrinolysis can enhance
bleeding potential and in some instances result in spontane-
ous hemorrhage.
Hemostasis progresses through three steps, beginning
with (1) vasospasm which occurs nearly simultaneously with
(2) platelet plug formation (referred to as primary hemosta-
sis), followed by (3) the development of a fibrin clot (second-
ary hemostasis) [1–3]. Each step is triggered by injury to the
blood vessel wall with resultant exposure to subendothelial
matrix constituents. As vascular spasm or vasoconstriction
helps limit blood loss from the vessel, primary and second-
ary hemostasis function together to form a fibrin clot.
Primary hemostasis is described in more detail in Chapter 1.
Secondary hemostasis, also referred to as blood coagula-
tion, is initiated by exposure of the plasma to tissue factor
(TF) [1]. TF is found in the subendothelial matrix and can
D. M. Adcock
LabCorp Diagnostics, Burlington, NC, USA
e-mail: Adcockd@LabCorp.com
B. F. Poirier (*)
Colorado Coagulation, Laboratory Corporation of America®
Holdings, Englewood, CO, USA
e-mail: poirieb@labcorp.com
© Springer Nature Switzerland AG 2021
J. Teruya (ed.), Management of Bleeding Patients, https://doi.org/10.1007/978-3-030-56338-7_2
2
also be expressed by select cells in response to certain stim-
uli. A trace amount of procoagulant factor VII circulates in
the activated rather than proenzyme form (activated factor
VII [FVIIa]), and this serves to keep the hemostatic system
“primed.” FVIIa binds exposed TF resulting in the activation
of factor X (activated FX [FXa]). This ultimately initiates the
sequential activation of multiple coagulation proenzymes
into functional serine proteases or functional cofactors, the
activated forms of the procoagulant factors. Activated proco-
agulant factors bind the activated platelet and red blood cell
surface, and this enables interaction with their respective
cofactors and required cations, allowing the generation of
highly efficient coagulation factor complexes that result in
bursts of thrombin formation. Thrombin cleaves soluble
fibrinogen creating fibrin polymers that polymerize electro-
statically. An insoluble fibrin gel is formed when activated
factor XIII covalently cross-links the fibrin polymers.
Most proteins involved in hemostasis are produced in the
hepatic parenchyma with the exception of factor VIII, which
is believed to be synthesized by hepatic sinusoidal endothe-
lial cells, and a subunit of factor XIII [4]. Due to hepatic
immaturity at birth, the normal reference interval for most
clotting factors varies with age, a concept coined “develop-
mental hemostasis” [5].
Laboratory Evaluation of Blood Coagulation
In the laboratory, secondary hemostasis is measured by
determining the time required for a fibrin clot to form in
platelet-poor plasma, when exposed to a coagulation activa-
tor and calcium. This system does not evaluate the platelet
component of hemostasis, nor does it reflect the activity of
the naturally occurring anticoagulants. Furthermore, lysis of
the fibrin clot is evaluated using a distinct set of assays.
Global screening assays that evaluate both the hemostatic
and fibrinolytic systems require whole blood testing and are
discussed in Chapter 5, “Hyperfibrinolysis.” In addition to
performing screening laboratory assays, the evaluation of a
11
12
bleeding patient should include a complete history, physical
examination, and review of medications, including pre-
scribed and over-the-counter preparations, as well as any
naturopathic remedies.
Secondary hemostasis can be evaluated using a simple
battery of three assays which should be performed in all
bleeding patients [1, 2]. These assays each measure the time
to fibrin clot formation following the addition of different
coagulation activators. The tests that evaluate secondary
hemostasis include the prothrombin time (PT), activated par-
tial thromboplastin time (aPTT), and functional fibrinogen
level or a thrombin time (TT) (a surrogate fibrinogen assay
when heparin is not in the specimen). In vitro, fibrin clot
formation can be initiated through the intrinsic system by
adding a contact activator (e.g., ellagic acid, silica, kaolin),
through the extrinsic system by adding tissue factor, or it can
be initiated by the addition of thrombin, each of which is
added to separate aliquots of the anticoagulated plasma sam-
ple [1]. Calcium is required to reverse the anticoagulant
effect of sodium citrate. Evaluation of functional fibrinogen
or a thrombin time is needed in the evaluation of a bleeding
patient, as the PT and aPTT are insufficiently sensitive to
clinically significant decreases in fibrinogen levels. Important
limitations of the PT and aPTT include the following: (1)
both assays can be prolonged factitiously due to a number of
different pre-analytical variables, (2) neither assay detects
abnormalities of certain critical factors such as factor XIII
and proteins in the fibrinolytic system nor platelet function
defects, and (3) either assay may be prolonged due to condi-
tions that do not increase bleeding risk [6]. A significant
limitation of these screening assays is that in vitro fibrin clot
formation does not adequately mimic the physiologic clot-
ting process and does not evaluate the interaction of plasma
factors with cellular components and the vasculature.
Although the PT, aPTT, and functional fibrinogen assay are
inadequate measures of in vivo hemostasis, these assays are
a convenient and readily available means to provide, albeit
limited, evaluation of secondary hemostasis.
Screening Coagulation Assays
Proper sample acquisition and handling is critical to obtain-
ing accurate coagulation results [7–9]. Samples should be
collected in 3.2% sodium citrate using the proper 9:1 blood
to anticoagulant ratio. Incomplete filling of a sodium citrate
tube, hematocrit >55%, or combining the contents of two
incompletely filled sodium citrate tubes may lead to spuri-
ously prolonged clotting times. While samples with hemato-
crits >55% require adjustment by reducing the amount of
liquid anticoagulant in the collection tube, no adjustment is
required for samples with reduced hematocrits. Samples
should be collected from a peripheral vein, whenever possi-
D. M. Adcock and B. F. Poirier
HMWK PK
FXII
FVII
FXI PT
Extrinsic pathway
FIX
APTT FVIII
Intrinsic pathway
FV
FX
FII Thrombin
Fibrinogen Fibrin
TCT
Fig. 2.1 In vitro model of secondary hemostasis
ble, to avoid contamination from a port or intravenous infu-
sion. Samples should be adequately mixed immediately
following collection and processed in a rapid fashion.
Hemolysis should be avoided as this may interfere with clot-­
based results.
The PT evaluates factors of the extrinsic pathway (factor
VII), common pathway (factors X, V, and II), and fibrinogen
(Fig. 2.1) [2, 3, 10]. In the PT assay, coagulation is initiated
by adding tissue factor and phospholipids (this combination
is called thromboplastin) to recalcified plasma, and the time
to form a fibrin clot is measured in seconds. Most PT reagents
contain a heparin neutralizer, and therefore the PT does not
typically elevate in the presence of heparin up to 1–2 units/
mL depending on the PT reagent. The aPTT evaluates factors
of the contact pathway (high molecular weight kininogen
[HMWK], prekallikrein [PK], factor XII), intrinsic pathway
(factors VIII, IX, and XI), and common pathway (factors X,
V, and II) as well as fibrinogen [2, 3, 10]. In the aPTT, fibrin
clot formation is initiated by addition of a contact activating
agent, calcium, and phospholipid.
Prolongation of the aPTT or PT typically occurs when a
single factor in the appropriate pathway falls below approxi-
mately 50% (a normal reference interval for factor activity is
often in the range of 50–150%). An important caveat to this
is that the aPTT is relatively insensitive to the clinically
important intrinsic factors (factors VIII, IX, and XI), and the
aPTT typically does not prolong until one of these factors
falls below about 30% [3, 10]. Reagent responsiveness to
factor deficiency varies between reagent manufacturers and,
therefore, between laboratories. The aPTT may also elevate
when multiple factors are in the lower end of the normal
range, especially in a pediatric patient [11]. Neither the aPTT
nor PT prolongation demonstrates a linear relationship with
2 Screening Coagulation Assays, Factor XIII and D-dimer 13

decreased factor levels, and these assays prolong in an expo- Table 2.1 Bleeding with a normal APTT and PT and TT/fibrinogen
nential fashion as functional factor concentrations decrease Cause Comment
[12]. The thrombin time measures the time to fibrin clot for- Mild factor VIII, factor Single factors generally have to fall
mation following the addition of thrombin. The thrombin IX, or factor XI below approximately 30% before the
deficiency aPTT is prolonged
time is an indirect measure of functional fibrinogen, and in
Hereditary or acquired Can lead to significant bleeding
the evaluation of a bleeding patient, either a thrombin time or FXIII deficiency potential with spontaneous bleeding
functional fibrinogen should be measured [13]. Functional Alpha 2-antiplasmin
fibrinogen is measured using a citrated plasma sample deficiency
exposed to thrombin in the presence of phospholipids and Abnormal platelet
calcium, which is called Clauss method. The time in seconds number or function
Vascular or collagen Such as Ehlers-Danlos syndrome,
for fibrin clot to form is read in relationship to a standard abnormality vasculitis
curve of known fibrinogen concentration [1]. Anatomical cause
Once it is determined that the aPTT, PT, and/or TT are
abnormal, plasma mixing studies can be performed to help
determine if the prolongation of the clotting time reflects a fac-
Table 2.2 Isolated prolonged PT (normal aPTT and normal fibrino-
tor deficiency or the presence of an inhibitor [2]. In the pres- gen/TT)
ence of a factor deficiency(ies), addition of an equal volume of Cause Comment
normal plasma to the patient plasma typically corrects the clot- Deficiency or inhibitor of Severe deficiency may be associated
ting time into the normal reference interval. In the presence of factor VII with spontaneous bleeding. Factor VII
a specific or non-specific factor inhibitor, addition of normal is the first factor to decrease with
plasma typically does not lead to correction of the patient clot- vitamin K deficiency or antagonism
and liver disease. Inhibitor is rare
ting time into the reference interval, although this is dependent
Mild deficiency of factor Single factor deficiencies in the
on the reagent and type of inhibitor. Some factor inhibitors, X, factor V, or factor II 30–60% range may lead to isolated
such as specific factor VIII and factor V inhibitors, often require prolongation of the PT. Moderate to
incubation at 37 °C for 1 to 2 hours in order to demonstrate severe deficiency causes prolongation
of aPTT as well
their inhibitory effect [14]. Specific factor inhibitors are anti-
Anticoagulant therapy: May cause prolongation of the aPTT
bodies that neutralize the activity of a single coagulation factor direct Xa inhibitor depending on drug concentration. Will
and often lead to a bleeding diathesis. These antibodies are anticoagulant (e.g., not affect the TT
detected and their strength measured in the laboratory using rivaroxaban, apixaban,
specific coagulation factor inhibitor assays commonly referred edoxaban)
to as a Bethesda assay [14]. Non-specific inhibitors interfere
with multiple factors or can interfere with a reagent component must fall to 20 to 40% or less, depending on the reagent used
such as phospholipid. Lupus anticoagulants and certain antico- in the assay and how the reference range is established,
agulant drugs including heparin, direct Xa, and direct thrombin before the aPTT prolongs [10]. FXIII activity, platelet dys-
inhibitor agents act as non-specific inhibitors in the coagulation function, and fibrinolytic factors are not assessed by these
laboratory and may lead to incomplete correction in normal screening assays. The most important contributors to bleed-
plasma mixing studies [14, 15]. In order to determine the basis ing that are missed by the PT and aPTT are platelet dysfunc-
of aPTT, PT, and/or TT prolongation, further testing such as tion and hyperfibrinolysis [16].
specific factor assays or evaluation for a lupus anticoagulant
may need to be performed.
Abnormalities of the aPTT and PT are common in the  rolonged PT, Normal aPTT, and Normal
P
critically ill as well as the trauma patient. In trauma patients, Functional Fibrinogen
a PT and/or aPTT ratio >1.5 (compared to the control) pre-
dicts excessive bleeding [16]. However, in trauma patients, When the PT is prolonged but the aPTT and functional
these parameters are not entirely useful within the first fibrinogen (or TT) are normal, a deficiency of factor VII
1–2 hours of the trauma or until the patient stabilizes [17]. In should be considered (see Table 2.2) [1, 2, 18]. Mild defi-
hypothermic patients, the values of the PT and aPTT may ciencies of factors X, V, and II may also cause isolated pro-
underestimate the coagulopathy because the PT and aPTT longation of the PT, as PT reagents are more sensitive to
reactions are performed on samples warmed to 37 °C [17]. deficiencies of these common pathway factors than are aPTT
A number of hemorrhagic diatheses may occur despite a reagents [19]. Certain drug therapies, such as direct Xa
normal aPTT, PT, and functional fibrinogen level (see inhibitor anticoagulants and warfarin, can cause isolated
Table 2.1). A normal aPTT does not rule out mild deficien- ­prolongation of the PT but can also prolong the aPTT with
cies of factor VIII, IX, and/or XI as these factor activities stable warfarin therapy [15, 20].
14
In the presence of factor deficiency, a PT mixing study
generally demonstrates correction unless the prolongation is
due to vitamin K deficiency, vitamin K antagonism, or some-
times liver disease, where the PT mixing study tends to dem-
onstrate near correction into the normal reference interval,
but not completely within the normal reference interval. For
example, if the normal interval of the PT is 11–14.1 seconds
and a patient has a PT result of 35 seconds, a mixing study
that demonstrates complete correction would have a 1:1 mix
result that falls into reference interval (11–14.1 seconds),
and one that demonstrates near correction may correct to a
PT of 14.2–15 seconds. A PT mix that demonstrates incom-
plete correction would have a 1:1 mix result usually above
about 18 seconds (with a normal reference interval of
11–14.1 seconds), and this occurs in the presence of a factor
inhibitor such as a FVII inhibitor. This may also occur with a
direct thrombin or Xa anticoagulant or can occur with a spe-
cific factor V, X, or II inhibitor, although each of these drugs
and inhibitors typically also elevates the aPTT [20–22].
Select factor II (prothrombin) inhibitors, specifically those
that occur in association with lupus anticoagulants, com-
monly function as clearing rather than neutralizing antibod-
ies [23, 24]. See Chapter 23. These antibodies cause
prolongation of the PT due to rapid clearance of the factor
II-antibody complex, resulting in low factor II levels and
hence factor II deficiency. A PT normal plasma mixing study
demonstrates correction as these clearing coagulation factor
inhibitors will not be detected with a factor inhibitor
(Bethesda) assay.
Factor VII has the shortest half-life of all coagulation
factors and therefore is the first factor to decrease with
liver disease as well as vitamin K deficiency or vitamin
K antagonists. Hereditary deficiency of factor VII is rare
as is the development of acquired inhibitors to FVII [1,
25, 26]. Deficiency of factor VII prolongs the PT without
affecting the aPTT or TT. A hereditary deficiency of any
of the common pathway factors (factors X, V, and II) is
rare [1, 25]. Heterozygous (mild) deficiencies of any of
these factors may or may not be associated with bleeding.
Bleeding is more typical of heterozygous factor II defi-
ciency than heterozygous factor V, VII, or X deficiency
[1, 25]. Spontaneous bleeding associated with these rare
heterozygous factor deficiencies typically involves skin
and mucous membranes. Heterozygous deficiency of fac-
tor V, X, or II may present with an isolated elevated PT
[19]. Homozygous deficiency of any one of the common
pathway factors would lead to significant factor deficiency
and cause prolongation of both the PT and aPTT and may
lead to a significant bleeding tendency, both spontaneous
and with provocation [25]. Acquired deficiency of factor
X can occur with amyloidosis and, depending on the level
of deficiency, may lead to an isolated, elevated PT and
increased bleeding risk [19].
D. M. Adcock and B. F. Poirier
 rolonged aPTT, Normal PT, and Normal
P
Functional Fibrinogen (or Normal TT)
Prolongation of the aPTT with a normal PT and functional
fibrinogen (normal TT) may reflect a deficiency or inhibitor of
a contact pathway factor (factor XII, HMWK, PK), deficiency
or inhibitor of an intrinsic pathway factor (factor VIII, IX, XI),
or the presence of a lupus anticoagulant (see Table 2.3) [1–3,
27]. Heparin therapy or contamination, as well as direct throm-
bin inhibitor (DTI) anticoagulants, elevates both the aPTT and
thrombin time [15]. Certain PEGylated drugs (e.g., PEG inter-
feron) may cause prolongation of the aPTT, yet this PEG inter-
ference poses no increased bleeding risk [28]. Select
lipoglycopeptide antibiotics including daptomycin and tela-
vancin may elevate the aPTT, and in some circumstances the
PT, without increasing bleeding risk [29, 30]. The degree of
prolongation depends on the concentration of the antibiotic in
the plasma and the reagent sensitivity to the drug. It has been
reported that elevated levels of C-reactive protein may cause
spurious elevation of the aPTT with commonly used aPTT
reagents [3]. Severe contact factor deficiencies typically
greatly prolong the aPTT, yet clinically are not associated with
an increased bleeding potential. Mild deficiencies of a contact
factor pathway generally will not affect the aPTT.
Table 2.3 Isolated prolonged aPTT (normal PT and TT/fibrinogen)
Cause Comment
Intrinsic factor (factor Severe deficiency may be associated
XI, factor IX, factor with spontaneous bleeding; aPTT may
VIII) deficiency or be normal with mild single factor
inhibitor deficiency
Contact factor (factor Severe deficiency may lead to marked
XII, prekallikrein, high prolongation of the aPTT, but no
molecular weight increased bleeding risk. Heterozygous
kininogen) deficiency or deficiency of a single contact factor will
inhibitor not likely affect the aPTT
Acquired factor VIII, Factor VIII inhibitor by far the most
factor IX, or factor XI common and may lead to severe
inhibitors spontaneous bleeding, can occur as
alloantibody (in hemophilia A) or
autoantibody; inhibitors against factor
IX or XI are rare
Lupus anticoagulant Increases risk for thrombosis and
(LA) obstetric complications. Leads to
bleeding only when LA is associated
with thrombocytopenia or deficiency of
prothrombin (factor II). Factor II
deficiency would cause a prolonged PT
Select PEGylated drugs Prolongation of APTT is not associated
with increased bleeding risk
Lipoglycopeptide Select agents effective against MRSAa
antibiotics, select such as daptomycin and telavancin.
Prolongation of aPTT is not associated
with increased bleeding risk. May also
prolong the PT depending on plasma
drug concentration and reagent used in
laboratory
Methicillin-resistant Staphylococcus aureus
a
2 Screening Coagulation Assays, Factor XIII and D-dimer
Table 2.4 Causes of factor VIII deficiency
Cause Comment
Hemophilia A X-linked; therefore typically males affected;
female carriers may bleed with provocation
von Willebrand In type 2N VWD, VWF activity and antigen
disease (VWD) may be normal and FVIII activity reduced
Acquired May be associated with severe spontaneous
hemophilia A bleeding
Acquired von May be associated with severe spontaneous
Willebrand bleeding
syndrome
Spurious decrease Can occur with some lupus anticoagulants or
incorrect sample type (i.e., serum or EDTA
plasma)
In a previously healthy male or female patient with a pro-
longed aPTT and normal PT and fibrinogen, who presents
with acute, possibly catastrophic, spontaneous hemorrhage
into soft tissues and muscle, acquired hemophilia (an acquired
factor VIII inhibitor) or acquired von Willebrand syndrome
(AVWS) should be considered (see Table 2.4) [31–34]. Factor
VIII inhibitors (acquired hemophilia A) can develop in an
older population for no apparent reason, or they may present
in patients with underlying autoimmune disorders, underlying
solid tumors, or lymphoproliferative malignancies and may
also occur in association with pregnancy [31, 32]. Acquired
hemophilia A should be considered early in the evaluation of
abnormal bleeding in the postpartum setting [35]. FVIII inhib-
itors may develop 1 to 4 months and rarely as late as 1 year
postpartum. Acquired factor VIII inhibitors are rare in children
but have been reported [36]. In the presence of a FVIII inhibi-
tor, the aPTT is elevated, while the PT is normal, and aPTT
mixing studies may or may not demonstrate correction upon
immediate mix, but typically demonstrate prolongation with
incubation over time at 37 °C. Factor VIII activity and FVIII
inhibitor (Bethesda) assays should be performed and also pos-
sibly von Willebrand factor activity and antigen assays (see
next paragraph). Acquired inhibitors to factor VIII are the
most frequent acquired factor inhibitors reported. Acquired
inhibitors to factor IX or XI are rare [37, 38].
Acquired factor VIII deficiency can also occur as a feature
of AVWS [34, 39, 40]. In a bleeding patient without a history
of hemophilia A, who has a low factor VIII activity (<10%),
von Willebrand factor antigen and activity should be mea-
sured to rule out AVWS, especially if there is no evidence of
a specific FVIII inhibitor. AVWS may occur in both pediatric
and adult patients [39]. There are many different underlying
conditions that are associated with AVWS such as underly-
ing lymphoproliferative disorders, certain cardiac valve dis-
orders, ventricular septal defects, essential thrombocythemia,
Wilms tumor, and hypothyroidism, to name a few. The labo-
ratory diagnosis of AVWS is essentially the same as heredi-
tary von Willebrand disease (VWD), and both type 1
(quantitative) and type 2 (qualitative) deficiencies may occur.
15
Congenital factor VIII (hemophilia A) and IX deficiencies
(hemophilia B) are X-linked disorders and therefore typi-
cally present in males and rarely in females (except in spe-
cific situations, e.g., skewed lyonization, homozygosity for
the hemophilia gene resulting from consanguinity, and dele-
tions such as Turner syndrome), with an isolated prolonged
aPTT and isolated deficiency of either factor VIII or factor
IX [41–43]. Severe hemophilia A or B (≤1% factor VIII or
IX activity, respectively) presents with spontaneous hemor-
rhage, while moderate (2–5% factor level) to mild (6–40%
factor level) hemophilia may go undiagnosed until a patient
is challenged. Hemophiliacs may develop specific factor
inhibitors in response to factor replacement therapy, and
when present this significantly complicates replacement
therapy. Female carriers of hemophilia A and B have an
increased bleeding tendency, even when factor levels are in
the 40–60% range, especially when their hemophiliac rela-
tives have a severe form of the disease [42]. Factor levels are
not always a good predictor of bleeding in hemophilia carri-
ers [44]. Recent studies have highlighted the increased inci-
dence of postpartum hemorrhage, in the range of 20–40%, in
this population [45].
Factor XI deficiency (hemophilia C) is autosomal in
inheritance and affects both males and females [46, 47]. The
incidence of factor XI deficiency in most populations is 1 in
1,000,000, although it is significantly greater in an Ashkenazi
Jewish population occurring at a frequency of 1 in 450.
Severe deficiency is defined by factor levels less than 15%.
The bleeding tendency is variable and does not always cor-
relate to factor XI activity levels, but is more likely to occur
with severe deficiency and when an injury involves an area
with high fibrinolytic potential, such as the oral cavity or
urogenital tract. Spontaneous bleeding with hemophilia C is
rare. Bleeding typically occurs only with provocation.
Development of inhibitors in response to replacement ther-
apy is unusual but reported. Acquired factor XI inhibitors are
rare and may occur in those with underlying autoimmune
disorders [37, 38].
VWD is the most common inherited bleeding disorder.
It has an autosomal mode of inheritance and therefore
affects both males and females. VWD is due to a deficiency
or defect of von Willebrand factor (VWF) [1, 40, 48, 49].
VWF serves as the carrier protein for procoagulant factor
VIII and also serves to bind platelets to the site of vascular
injury, and therefore, VWF serves an important role in pri-
mary hemostasis. When VWF is decreased, factor VIII
activity is decreased concordantly. The aPTT is not an ade-
quate screen for VWD as the aPTT will not prolong until
factor VIII levels fall below 20–30%, depending on the
reagent [10]. To screen for VWD, VWF antigen and activ-
ity, as well as factor VIII activity, should be measured in
plasma. Deficiencies of VWF alone do not affect the aPTT,
PT, or thrombin time.
16
Lupus anticoagulants (LA) are a common cause of an iso-
lated prolonged aPTT. Although historically termed an “anti-
coagulant,” lupus anticoagulants are more commonly
associated with an increased thrombotic risk and risk of cer-
tain obstetric complications, rather than increased bleeding
risk [27, 50]. LA are non-specific inhibitors, and aPTT mix-
ing studies generally demonstrate incomplete correction,
although this is reagent dependent. Diagnosis of the presence
of LA is made by comparing the results of phospholipid
dependent assays performed in the presence of low and high
phospholipid concentrations. Shortening of the clotting time
in the presence of increased phospholipids is characteristic
of LA [27, 50]. As PT reagents contain a greater phospho-
lipid concentration compared to aPTT reagents, most PTs
are not prolonged in the presence of LA, although certain PT
reagents may demonstrate sensitivity to lupus anticoagu-
lants. Lupus anticoagulants may interfere with the phospho-
lipids required in factor VIII, IX, and/or XI activity assays,
making the activities appear factitiously low. Assay interfer-
ence should always be considered in a patient without bleed-
ing, but with decreased factor VIII, IX, and XI activity
results, especially when the values of all three factors are
low. If LA interference is suspected, a chromogenic factor
VIII or factor IX activity assay should be used as these assays
are more accurate in the presence of LA [51]. Another option
is to measure the intrinsic factors using an aPTT reagent that
is not LA sensitive, and this may require sending the sample
to a reference laboratory. In contrast to spurious LA interfer-
ence in intrinsic factor assays where factors VIII, IX, and XI
may appear decreased, severe liver disease is associated with
decreased factor IX and XI activities but normal to elevated
factor VIII activity. In vitamin K deficiency/antagonism, fac-
tor IX activity is low and factor VIII and XI activities are
normal.
Prolonged TT, Normal PT, and Normal aPTT
In practice, this pattern of results occasionally occurs due to
the presence of low molecular weight heparin or unfraction-
ated heparin (either from low-dose therapy or contamina-
tion) or direct thrombin inhibitor (DTI) therapy (see
Table 2.5) [20]. As drug concentration increases, the aPTT
will elevate with heparin, and both the aPTT and PT prolong
in the presence of DTI [15]. In fact, many laboratories per-
form a thrombin time as a quality control measure in an
effort to rule out heparin therapy or contamination of a sam-
ple. In general, conditions or drugs that prolong the thrombin
time that would lead to spontaneous or an enhanced bleeding
diathesis would also elevate the PT and aPTT. The thrombin
time is sensitive to both the amount and functionality of
fibrinogen. Thus, both hypofibrinogenemia and dysfibrino-
genemia may elevate the thrombin time [1, 52, 53]. Typically,
D. M. Adcock and B. F. Poirier
Table 2.5 Isolated prolonged TT (normal aPTT and normal PT)
Cause Comment
Deficiency of Fibrinogen levels less than approximately
fibrinogen 100 mg/dL result in prolongation of the PT
and aPTT. The PT is more sensitive to low
fibrinogen than the PTT
Abnormal Tends to cause prolongation of the PT and
fibrinogen aPTT, although the TT is the most sensitive
(dysfibrinogen) assay. May be associated with major
hemorrhage
DOAC of anti-Xa The PT and aPTT may be prolonged or
action normal
Fibrin split products Interferes with fibrin polymerization and
at high may lead to prolongation of the PT and/or
concentration aPTT, although TT is most sensitive. Does
not increase bleeding risk by itself
Monoclonal Interferes with fibrin polymerization and
antibodies, select may lead to prolongation of the PT and/or
aPTT, although TT is most sensitive. Does
not increase bleeding risk by itself
the aPTT and PT will elevate when fibrinogen levels fall
below around 80 to 100 mg/dL, but this depends on the
reagent used in the laboratory.
Substances that can interfere with fibrin polymerization
such as fibrin(ogen) degradation products and paraproteins
may elevate the TT, but are not consistently associated with
an enhanced bleeding potential [54]. Interference with fibrin
polymerization may also cause prolongation of the aPTT and
PT, although the TT is the most sensitive of the three assays.
Inhibitors of thrombin activity, such as antibodies to throm-
bin formed after exposure to thrombin glue, may elevate the
TT but typically elevate the aPTT and PT as well [55].
Increased level of D-dimer is another cause of the prolonga-
tion of the TT.
 rolonged PT and Prolonged aPTT, Normal
P
Functional Fibrinogen (or Normal TT)
Prolongation of the PT and aPTT with a normal functional
fibrinogen (or normal TT) may reflect multiple factor defi-
ciencies, a deficiency or inhibitor of a common pathway fac-
tor (factors X, V, and II), vitamin K deficiency, vitamin K
antagonist (warfarin), superwarfarin (rat poison), or an anti-
­Xa inhibitor anticoagulant (see Table 2.6) [1–3, 15, 20, 56].
Some lipoglycopeptide antibiotics, such as daptomycin or
telavancin, may elevate the aPTT and PT, presumably due to
interference with the phospholipids required in the assay, but
are not associated with an increased bleeding risk [29, 30].
aPTT and PT mixing studies demonstrate correction with
factor deficiency(ies). An exception to this is factor II inhibi-
tors that develop in association with a lupus anticoagulant as
these antibodies are clearing and not neutralizing [23, 24].
Incomplete correction of both aPTT and PT mixing studies
Another random document with
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is doubtful whether they would have succeeded had it not been for
the help of the friendly Esquimaux, who did everything in their power
for their visitors.
At one time, they all gave up the ship as lost. The ice closed
around them with such a crushing force, that the captain and crew
fled to the shelter of the Esquimaux snow houses, where they were
most hospitably received, and preparations were made to entertain
them all winter.
But the vessel escaped, it seemed, almost by a miracle, and the
crew returned to it very soon. Then the ice broke up into smaller
pieces and drifted away towards the open sea, and the ship
prepared to follow as soon as the channel should be sufficiently
open. The Esquimaux bade farewell to the whalers, and went off on
an expedition, partly for hunting, but chiefly to gather in their dogs
and reindeer under shelter for the winter, leaving a few old men and
boys to guard the settlement.
Polargno happened to be one of the boys left behind. The day
after the expedition started he walked down to the shore to see if the
bay was sufficiently open for the ship to start on its voyage. He found
that the vessel was enclosed in thin ice which extended for quite a
distance beyond in a solid sheet. But, as the weather was still
moderating, this ice would probably break up in a few hours. Some
sailors were packing up their things in a tent they had occupied on
the shore. They evidently expected certainly to get away this time.
But, before Polargno reached the place, they ran out of the tent, and
down towards the beach with exclamations of horror. Polargno ran
after them, and soon discovered the cause of their excitement.
Lower down could be seen the open sea, and, rising and falling on
the waves were blocks of ice, some large and some small. On one of
the largest floes stood a sailor, trying to ward off the attack of a polar
bear. The bear had evidently just arrived upon the scene, and was
walking around the man, preparatory to making a rush upon him. If
he once closed with the sailor there was small chance of the latter
escaping with his life. The ice floe, on which they both stood, was
now almost stationary, having become wedged in a mass of light,
loose pieces that were swaying back and forth on the water.
Having taken in this situation at a glance, Polargno did not hesitate
an instant, but ran down the shore at his best speed to a spot
opposite the ice-floe. The four sailors followed, but they could not
equal the speed of the Esquimaux boy, and when they arrived he
had taken off his outer suit and boots, retaining only his in-door suit,
and light seal-skin boots. The sailors could not imagine what the boy
was about, but their attention was absorbed in their comrade who
was in such deadly peril, and they paid little heed to Polargno. Two
of them had guns, but they found to their dismay, that these were of
no use. The distance was too great for them to aim at any particular
spot of the beast’s body, and a polar bear is very hard to kill, unless
a vital part is struck. If he were only wounded he would be so
infuriated that the sailor’s case would be hopeless. And, besides, the
bear was now on the farther side of the block of ice, and was thus
partly covered from their fire by the man’s body.
All this had passed in the space of a very few minutes; and now,
while they were wondering what they could do, and watching for a
chance to fire, the sailors suddenly discovered that the Esquimaux
boy was far on his way to the help of their comrade. He had made no
boast of what he was going to do. He had asked for no help. He
knew they could not give him any. The thin cakes of ice, which
dipped into the water under his light tread, would have sunk with the
weight of one of the sailors. He saw that a fellow-creature was in
danger of being killed by a ferocious animal; and, at once, without a
care for his own personal safety, he went to the rescue. He had, in
his belt, his knife and his hatchet, and, on these, and his dexterity
and quickness, and knowledge of the ways of polar bears, he relied
for success.
The sailors watched him, full of admiration for his courage, and for
his skill in jumping the floating cakes of ice that one would scarcely
expect to bear the weight of a bird. He seemed to select the largest
and strongest pieces, by a sort of quick instinct, and bounded from
one to another as lightly as a cat. A foot went into the water at nearly
every step, but he did not sink.
 Meantime the bear had advanced upon the sailor, who, it now was
seen, had a knife in his hand, prepared to do his best.
The Esquimaux boy had now reached the pack of loose ice
against which the ice floe had rested. This was firm, and he paused
an instant, before springing on to the floe. The sailors thought his
courage had failed at the last moment. But no! Polargno knew there
was no time to lose, and he required only this instant to see where
he could best strike the bear. There was no vital part at which he
could get a good stroke. All he could do at first was to divert the
bear’s attention from the sailor to himself.
He threw his hatchet straight at the side of the bear that was
exposed to him. It sank through the tough skin into the flesh, but the
wound was not a very severe one. The astonished animal turned,
and, seeing the boy who had now sprung upon the ice floe, not a
dozen yards from him, he made towards this new comer in a great
rage.
But Polargno was ready for him. He sprang aside, and quickly
struck his knife into the side of the bear. The animal fell, but was not
killed, and it tried to stagger up again; but, by this time, the sailor had
recovered his senses, for he had stood apparently stupefied when
the bear left him. He now came to the boy’s assistance, and,
together, they soon put an end to their formidable foe.
Polargno pulled off his hood, and waved it in the air, and shouted
“Hurrah!” This word and action he had learned from the sailors. By
this time the whole crew had come down from the ship, and they
also joyfully waved their hats, and shouted “Hurrah!”
But the two must be taken off the ice-floe before it went sailing out
into the sea. The pack of ice was, even now, moving faster, and gave
signs of breaking up. So a boat was got down from the ship as
speedily as possible, and some of the sailors, steering in and out of
the floating ice, went to their relief, and took them safely to the shore.
They intended to leave the carcass of the bear, but it went to
Polargno’s heart to see so much good meat wasted, and he begged
so hard for it, that the sailors waited long enough to tow it to shore,
though they were in a hurry to get back before the upper ice field
broke up.
You may wonder how the sailor and the bear got off on this ice-floe
together; as you, no doubt, feel sure they did not make an
appointment to meet there. The sailor told how he came there. It
happened this way: The day before, he had lost a small wallet,
containing some of his valuables, among the ice hummocks near the
shore. As soon as he discovered his loss he searched for the bag,
and his companions aided him. It could not be found, and, this day,
while the men were occupied in packing up the last of their effects,
he went out on the ice to look once more among the hummocks for
his wallet. He wandered some distance out, but the ice was solid and
firm. Suddenly he heard a noise like a sharp thunder clap, and the
next instant he was floating out into the open sea, with blocks of ice
swirling and tumbling about him in all directions. The ice had broken
loose, and there was no way for him to reach the shore. He called
and shouted, but his cries did not reach the ship, or the men in the
tent. He was afraid the floe he was on would go to pieces before he
could be rescued, and he knew it would be impossible for him to
swim through the masses of loose ice. His swift course was
fortunately arrested by the ice-pack, and he hoped there would be
time to rescue him before it was all swept away by the waves, as he
was sure he must soon be missed by his companions in the tent.
Just as he was comforting himself with this thought, he turned, and
saw a large polar bear sitting upon its haunches very near him, and
regarding him attentively.
As the polar bear is dead, and as he was not able to tell his own
story, either living or dead, in any language that we could
understand, I cannot inform you how he came to be sailing out to
sea on a cake of ice. But there he was, and greatly alarmed was the
sailor when he caught sight of him. He had the presence of mind,
however, not to make any sudden motion, and hoped by keeping
very still, to persuade the bear that he was only an inanimate object.
But the creature knew better than that. It is probable he had been
observing the sailor for some time, and the reason the man did not
notice the beast was because it was so nearly the color of the ice
hummocks. It soon crossed over to his ice-floe, and it was then that
the men in the tent first saw what had happened to their companion.

THE ICEBERGS CLOSED AROUND THE SHIP.

You may be sure the sailor was deeply grateful to the Esquimaux
boy. He had nothing to give his preserver, but he wanted to take him
home with him to New England, and take care of him ever after. But
nothing would induce Polargno to leave his beloved Greenland. The
captain, and such of the crew as had anything to give, loaded
Polargno and his parents with gifts. The parents took them all, but I
think they were very much surprised at this munificence, and at the
praise that the white men showered upon the boy for his brave deed.
They were very much pleased that he should have behaved so well
when called upon to do his duty; but it did not occur to them,
apparently, that he could possibly have done otherwise than he did,
though they admitted that it was a bold deed to go out single-handed
to fight a polar bear. The Esquimaux are a very brave people.
Courage is such a common quality among them that it excites no
surprise. But, of all their foes, the one they dread most is the polar
bear. But then here was a man in danger of being killed by a bear,
and the boy went to his assistance as a matter of course. That was
the way they looked at it.
They all had plenty of time to talk this over, for the ship did not get
away for a week after the hunting party returned. The ice closed
around it again; and again the sailors made up their minds to winter
there. The Esquimaux had told them of two ships that had remained
there too late the years before, and had become enclosed in
icebergs. Great masses of these icy mountains, descended upon the
doomed ships. The crews worked hard to get the ships free, even
dragging them out from among the icebergs on one occasion with
ropes. But it was all in vain. The vessels were destroyed, and the
crews lost all they had. The Esquimaux took them in their sledges to
a lower settlement, where they found a whaling ship that conveyed
them home. The ships were probably all gone now, and if this vessel
was in like manner destroyed, these sailors would be compelled to
stay all the season with the Esquimaux.
But, one day, the ice broke up with a great noise, and disappeared
as suddenly as it came, and the vessel sailed out of the bay in a
clear channel, the sailors having promised to return next year if they
could.
And, in a short time, snow and ice, and winter, and darkness
enveloped the place.
 But the Esquimaux did not care. They were used to it. They did
what work they could. They had abundant stores for the winter. And
they sat around their lamps, and told stories of the wonderful
adventures they had passed through, or heard of.
Polargno, we are agreed, is not handsome to our American eyes;
and he does not know how to read and write; and never even heard
of geography and arithmetic. And yet, I wonder how many well-
taught American boys would so bravely and unselfishly risk their
lives to save the life of another.
 TURTLES AND THEIR EGGS.

MATAMATA TURTLE.
How would you like this pretty creature for a pet? He can be
domesticated, and will stay with you very contentedly, if you put him
in a place where he can’t get away. If you leave an open gateway,
however, the chances are he will walk out of it some day, and return
no more. He does not go away because he is tired of being petted,
for he likes that; or because he does not like you, for perhaps, in his
heart, (if he has one) he is sorry to part from you. He goes simply
because he can. This restless disposition moves him to extend his
travels; and, no doubt, he intends to return at some future day. But
he never does.
If you have him in any place where he can do mischief you had
better keep an eye on him; otherwise he will be poking his long nose
into things that do not concern him in the least.
His two ends are not well balanced, his neck being so very long,
and his tail so very short! The fringe-like appendage hanging from
his neck gives it somewhat the appearance of a great centipede.
His small eyes have not a very intelligent expression, but our
matamata has quite sense enough to take very good care of himself.
His shell is really very pretty. It looks as if it were hung loosely
upon him for a canopy, and as if he might be just as well off without
it, especially as it must be somewhat heavy to carry around on all
occasions. But, if you consulted him upon the matter of removing it,
he would, at once, object. Probably he would draw his long neck
instantly within his shell, leaving not so much as the tip of his sharp
nose visible; then he would whisk in his ridiculous tail; and, lastly, in
would go his fat legs and feet; and there he would have as tight and
snug a house as possible.
Did you ever eat any turtles’ eggs? If not, I advise you to do so on
the first opportunity, for they are very good.
The turtles lay their eggs in the sand that the heat of the sun and
sand combined may hatch them at the proper time. As soon as they
are hatched the young turtles make their way to the water, where
they know how to provide their own living, without instruction. But, in
the warm countries, where turtles abound, it is a wonder that any
young ones manage to get out of their eggs.
For the eggs are esteemed such a luxury, that, as soon as the
laying season of the turtles is over, the natives turn out in great
numbers, and search the sands for eggs, which they collect by the
thousands, for sale, and for their own eating.
 SEARCHING THE SAND FOR TURTLES’ EGGS.
It is at this laying season that the South American Indians capture
great numbers of turtles. The turtles come out of the water at night,
in crowds, for the purpose of depositing their eggs. They dig
trenches in the sand; and, having placed their eggs in these, and
covered them, they all make a grand rush back to the water. Then
the Indians, who are on the watch, run after them, seize as many as
they can get hold of by the tails, and throw them over on their backs.
In this position a turtle is helpless, and the Indians can easily kill
them.
The flesh is excellent food; but what the Indians chiefly desire to
possess is the fine yellow fat with which the turtles are well supplied.
From this fat the Indians manufacture a superior kind of oil, for which
they find a ready sale.
If these turtles were as large as some of the West Indian turtles
that have been brought to this country, the Indians would not have
an easy task in turning them over.
 A FEW VOLCANOES.

A mountain with its great cone smoking like a chimney, or sending

up into the clouds a grand sheaf of flame, must be a splendid sight,
and one never to be forgotten. But when it begins to pour forth rivers
of hot lava it is time to get entirely out of sight of it, if you can. For
these streams of lava are sometimes very long.

RIVER OF RED-HOT LAVA FROM MOUNT ETNA.

A hundred years ago Etna poured forth such an immense river of
fiery stones, and liquid lava, and threw it out with such violence that
it rushed in cascades and whirling torrents for fifteen miles, burning
up everything in its course, until it finally plunged into the sea.
 This volcano has
an eruption once in a
while, but does not
often give the world
such a terrible one as
this. Sometimes the
lava only destroys the
fields and vineyards
near the mountain. It
is a small volcano,
but it has done a
good deal of damage.
Two hundred years
ago it entirely
destroyed the town of
Catania.
At a short distance
from it stands another
small volcano, which
is famous for the ruin
it has caused. You
have no doubt read
of the destruction of
the city of Pompeii;
and how it was
entirely buried under
the ashes thrown
from Vesuvius during
an eruption. Nearly
everybody in the
ERUPTION OF COTOPAXI IN 1741.
place at that time
perished, and now
people have to dig many feet under the ground to find the houses of
the buried city. A smaller city in the neighborhood, Herculaneum,
was buried at the same time, by the shower of ashes.
 This happened eighteen hundred years ago. But Vesuvius has not
been quiet ever since that time. There have been several eruptions.
In 1794 it hurled out torrents of fire from its top which rolled over a
town, a few miles distant, and burned it into ruins. Strange to say, the
town was rebuilt; and, a few years ago, Vesuvius visited it again with
a fiery flood, which, however, only destroyed part of the town.
A very much larger volcano, Cotopaxi, has, at different times, had
most frightful eruptions, but on account of its situation, has not done
so much damage as Etna and Vesuvius.
Just before an eruption occurs dull roars are heard inside of the
mountain, which seems to shake with the action of the lava boiling
up within it. Presently columns of smoke shoot up, then sheafs of
flame rise into the air with masses of cinders, and burning rocks. And
then the lava-streams pour over the sides, and roll down into the
plains.
Some volcanoes are always smoking when not in active eruption,
but the active volcanoes usually take long rests. The people who live
on, or near these burning mountains rely upon this fact for safety.
But it is not a very safe reliance, for their periods of rest are very
irregular; and they may break forth when least expected.
The greater number of these mountains throw out flames and lava,
but some send out hot mud instead, and others boiling water.
There are volcanoes that seem to have burned themselves out,
and are said to be extinct. Men can go down into the craters of
these, from whence the flames, and lava formerly issued, and
examine them. Some of these immense holes, or craters are now
filled with forests, and in others there are lakes. Others again are
nothing but rocky ravines.
Orizaba, in Mexico, is an extinct volcano, with a monstrous crater.
Persons standing on the opposite sides of this crater can barely see
each other, the distance between them is so great.
 CRATER OF ORIZABA.
The small volcanoes are more active than the large ones. Little
Stromboli is nearly always sending up flames, while the lofty
Cotopaxi is quiet sometimes for a century.
 THE ABSENT-MINDED BOTANIST.

The learned Mr. Nathaniel P. Reed, a native of New Jersey, and a

man well known to all the botanical and agricultural societies of the
civilized world, had, in the course of some thirty years spent in
patient and careful investigation into the structure and habits of
plants, acquired the power of completely abstracting his mind from
all its surroundings while engaged in his favorite pursuit. This was
often a very fortunate thing for him. But then, again, sometimes it
was very unfortunate.
He traveled everywhere, searching for specimens of plants. He
never seemed to get tired of this study. Over hot, sandy deserts, and
through savage forests he went undaunted; and, if he found a new
flower, or tree, he felt he was fully rewarded.
At last, he reached Cape Town in Southern Africa, a region he had
never before visited. A party of European hunters was just on the
point of starting on an expedition into the woods and jungles, and, in
an evil hour for them, asked Mr. Reed to join them. He at once
accepted the invitation, for it was a fine opportunity to hunt up new
plants.
I say it was in an evil hour that the hunters asked him because he
gave them so much trouble through his absent-mindedness. He was
a very entertaining traveling companion when not engaged in his
botanical studies, and so good-humored, and obliging that his
comrades did not grumble very much at the trouble he gave them.
But, nevertheless, he did cause them great anxiety, for they found
out that when he was searching for plants, or had a flower in his
hand analyzing it, he would put himself into situations of great peril
without knowing anything about it. And so, at least one of their
number always had to be on the lookout for Mr. Reed, to keep him
out of mischief.
For one thing, he would stray away from the main body. This was
against the rules of the expedition, for, in a forest full of wild beasts it
was necessary to keep together. Generally, when he wandered off
this way, he would be missed, and brought back before he had got
entirely out of sight. But, on three occasions, he managed to get lost,
without intending anything of the kind, and each time, he met with a
remarkable adventure.
The party had been out but a few days when he was lost for the
first time. He must have been absent two hours, when his
companions first missed him. At least no one could remember
having seen him for that length of time. What might not have
happened to him in those two hours, everywhere surrounded by
dangers? They immediately commenced the search for him.
They went back over the route they had traveled, and, at last,
found the place where Mr. Reed had left the caravan. They knew it
by the trampled bushes, and by the twigs broken off here and there,
and plants pulled up by the roots. Following these marks of his
progress they suddenly came out upon the banks of a river. And
there they saw the botanist. And, at the same time, all were struck
with horror at his situation. He, alone, was happily serene,
unconscious that any danger was near him.
Seated on a mossy bank, in the midst of tall reeds, on a peninsula
that extended pretty far out into the river, was their botanist. He had
an umbrella over his head to shield him from the sun, and was busily
engaged, arranging some “specimens” in his book of plants, which
he called an Herbarium. His back was towards the river, and so
absorbed was he in his occupation that he had not discovered that a
whole colony of crocodiles had come to pay him a visit. Neither did
he hear or see his companions although his face was turned directly
towards them.
The crocodiles had arranged themselves in a long row, with their
heads above the water, watching the botanist with great interest, and
evidently, meditating an attack upon him. How long they had been
there could not, of course, be known, but, in a few moments after the
hunters appeared upon the scene, the nearest crocodile seemed to
have made up his mind that a botanist was good to eat, and made
straight towards the land, followed by another huge beast.
 THE UNCONSCIOUS MR. REED.
Mr. Reed continued calmly to arrange his specimens.
Two men from the hunting party at once rushed forward upon the
peninsula, and fired upon the crocodiles. It was quite time, for two of
the foremost ones had reached the land. They rolled over into the
water, and all of the great beasts at once disappeared under the
surface of the river.
 The shots did arouse Mr. Reed’s attention, or else he had finished
his work; for he looked up, and said to his companions, who now
surrounded him:
“I have found one of the rarest of plants—the Iscodextiana—and it
has twelve stamens, just as I have always maintained.”
“I wonder if it would have agreed with the stomach of a crocodile!”
said one of the hunters.
Mr. Reed was so alarmed at the account of the peril to which he
had exposed himself, that it was a long time before he again
wandered from the caravan. The party had then formed a camp on
what was considered good hunting ground—that is in a forest
frequented by wild beasts. The hunters were successful in killing a
good many of these, and enjoyed the dangerous sport very greatly.
Meanwhile Mr. Reed continued his peaceful hunting of the wild
flowers, which grew all around in the most lavish profusion.
There were always some men left in the camp to guard it. One
day, when the hunters had returned, and were gathering around the
supper table, they missed Mr. Reed. On questioning the men who
had had charge of the camp, they could not remember when they
had last seen him. It was evident that he had wandered off to a
distance. If he got into one of his fits of abstraction there was no
knowing when he would ever find out he was lost, and try to get back
again.
Hastily swallowing some supper, a party of men went out in search
of the lost botanist, but were obliged to return to the camp without
him, for night came on, and the darkness was intense, and they
could not continue the search.
They retired to rest with heavy hearts, for they greatly feared their
very troublesome but very pleasant companion would fall a prey to
some wild beast. The sentinels on guard kept peering out into the
black forest, hoping to see the figure of their missing companion.
They kept up great fires as beacons to guide him to the camp.
In the middle of the night the whole camp was aroused by the
cries of the sentinels. The forest to the south of them was on fire.
The wind was high, and as there were many dead trees, and a great
deal of dry wood lying on the ground, the flames spread with great
rapidity. The hunters were not afraid that it would come their way, as
the wind blew it in an opposite direction. So they enjoyed the grand
spectacle.
In an hour the fire had extended through the woods for several
miles. The howls, and shrieks, and bellowings of hyenas, jackals,
lions, and tigers filled the air, as the frightened animals rushed out of
the flaming forest. A huge black form would sometimes loom up
against the red sky, and then seem to sink away into the darkness.
This was an elephant seeking refuge from the flames.
The hunters had watched the conflagration some time, when they
saw the figure of a man running towards them from the burning
woods. It was Mr. Reed! He had not been able to find the camp, he
said, until the fiery forest had made everything so bright that he
clearly saw the huts and tents from a long distance.
It appeared that he had lost his way while botanizing, but had
started on his return, confident he could follow his own trail back. But
he soon saw what he considered to be a flower. If so, it was larger
than any known to botanists. However he was not sure but it might
be a brilliantly colored mushroom. He forgot everything while
examining this, until, to his surprise, he found he could not see it.
Night had come on! He collected a quantity of dry wood into a heap,
and taking a match from his pocket applied it to the wood. This gave
him a bright light for the further examination of the plant.
He did not know how long it was after this that he discovered he
was nearly surrounded by burning wood, and that the forest was
roaring and crackling in front of him. He beat a retreat with all speed.