Practical Hemostasis and Thrombosis E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
Designed as a practical, succinct guide, for quick reference by clinicians with everyday questions, this title guides the reader through the range of approaches available for diagnosis, management, or prevention of hemorrhagic and thrombotic diseases or disorders.
- Provides essential practical management for all those working in the field of hemostasis and thrombosis
- Includes new chapters on direct oral anticoagulants, acquired inhibitors of coagulation, and expanded discussion of thrombotic microangiopathies
- Covers in a clear and succinct format, the diagnosis, treatment and prevention of thrombotic and haemostatic disorders
- Follows templated chapter formats for rapid referral, including key points and summary boxes, and further reading
- Highlights controversial issues and provides advice for everyday questions encountered in the clinic
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Veröffentlichungsjahr: 2016
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Table of Contents
Title Page
Copyright
List of Contributors
Chapter 1: Basic Principles Underlying Coagulation
Healthy Vasculature
Initiation
Amplification
Propagation
Localization
Coagulation Assays
Summary
References
Chapter 2: Laboratory Tests of Hemostasis
Introduction
Sample Collection and Processing
Use of Coagulation Screening Tests
Mixing Studies
Clotting Factor Assay Design
Thrombophilia Testing
Quality Assurance
References
Chapter 3: Molecular Diagnostic Approaches to Hemostasis
Introduction
Molecular diagnostics of bleeding disorders
Hemophilia A
Hemophilia B
von Willebrand disease
Less common inherited coagulation factor deficiencies
Inherited platelet disorders
Molecular diagnostics for thrombotic disease
Inherited resistance to activated protein C: factor V Leiden
Prothrombin 20210 3′ noncoding sequence variant
Thermolabile C677T 5,10-methylene-Tetrahydrofolate reductase variant
Deficiencies of Antithrombin, protein C, and protein S
The role of genetic testing in the clinical management of oral anticoagulation
The future for diagnostic molecular hemostasis
References
Chapter 4: Tests of Platelet Function
Structure of Platelets
Function
Classification of Platelet Defects
Platelet Function Testing
Global Tests of Platelet Function
Diagnostic Tests
Conclusion
References
Chapter 5: Evaluation of the Bleeding Patient
The bleeding history
Bleeding score
The physical examination
Laboratory evaluation
Final integration of clinical and laboratory data
Conclusion
References
Chapter 6: Hemophilia A and B
Introduction
Factor VIII Gene and protein
Factor IX gene and protein
Severity and symptoms
Inheritance
Making the diagnosis
The neonate with hemophilia
Clinical manifestations and their treatment
Treatment
Acquired hemophilia A
The future
References
Chapter 7: Von Willebrand Disease
Introduction: the von Willebrand factor
Physiological role of VWF
Classification of VWD
Genetics and molecular biology of VWD
Prevalence and frequency of subtypes of VWD
Clinical manifestations
Diagnosis of VWD
Management of patients with VWD
Conclusions
References
Chapter 8: The Rarer Inherited Coagulation Disorders
Introduction
Genetics
Clinical Features
Pregnancy
Investigation
Individual Deficiencies
Illustrative Case Histories
Conclusion
Acknowledgments
References
Chapter 9: Acquired Inhibitors of Coagulation
Introduction
Pathophysiology of Acquired Hemophilia, Acquired Von Willebrand Syndrome, and Other Acquired Coagulation Factor Deficiencies
Epidemiology
Signs and Symptoms
Diagnosis – Laboratory Measures to be Complemented with Clinical Findings
Differential Diagnosis
Management of Coagulation Inhibitors
References
Chapter 10: Quantitative Platelet Disorders
Introduction
Platelet Production
Mechanisms of Thrombocytopenia in Children and Adults
Evaluating a Thrombocytopenic Patient
Specific Conditions
Thrombocytopenia in the Newborn Infant
Thrombocytosis
Acknowledgement
References
Chapter 11: Qualitative Platelet Disorders
Introduction
Congenital Qualitative Platelet Defects
Abnormalities of the Platelet Receptors for Adhesive Proteins
Abnormalities of the Platelet Receptors for Soluble Agonists
Abnormalities of the Platelet Granules
Abnormalities of Membrane Phospholipids
Miscellaneous Abnormalities of Platelet Function
Acquired Platelet Defects
Therapy
References
Chapter 12: Disseminated Intravascular Coagulation
Introduction
Etiology
Pathogenesis
Clinical Manifestations
Diagnosis
Treatment
References
Chapter 13: Thrombotic Microangiopathies
Introduction
Confirmation of Diagnosis
Pathophysiology
Diagnosis
Treatment
Outcomes
References
Chapter 14: Venous Thromboembolism
Pathogenesis of Venous Thromboembolism
Prevalence and Natural History of VTE
Management of VTE
Treatment of VTE
Prevention of VTE
References
Chapter 15: Myeloproliferative Neoplasms: Thrombosis and Hemorrhage
Introduction
Clinical Manifestations
Diagnosis
Pathophysiology of Thrombotic and Hemorrhagic Complications
Treatment – General Approach
Treatment – Specifics
Patient Resources
References
Chapter 16: Arterial Thrombosis
Introduction
Risk Factors
Laboratory Investigations
Treatment
Conclusions
References
Chapter 17: Anticoagulation: Heparins and Vitamin K Antagonists
Heparins
Oral Anticoagulants: Vitamin K Antagonists
References
Chapter 18: The Direct Oral Anticoagulants
Pharmacology (Table 18.1)
Evidence-Based Clinical Indications
Practical Considerations
Future Directions
References
Chapter 19: Antiphospholipid Syndrome
Introduction
Definition of Antiphospholipid Syndrome
Antiphospholipid Antibodies and the Pathology of the Antiphospholipid Syndrome
Clinical Features of APS
Diagnosis of Antiphospholipid Syndrome
Treatment of APS
References
Chapter 20: Cardiovascular Medicine
Introduction
Acute Coronary Syndromes
Peripheral Arterial Disease
Ventricular Assist Devices
Electrophysiological Catheter Ablation
Transcatheter Aortic Valve Replacement
Conclusion
References
Chapter 21: Cardiothoracic Surgery
Introduction
Cardiac Surgery without Cardiopulmonary Bypass
Anticoagulation during CPB
CPB technical Aspects
Conventional Tests of Coagulation
Near-patient Testing-based Transfusion Algorithms
Blood and Hemostatic Component Management: Future Development
Preoperative Assessment Clinics
References
Chapter 22: Neurology
Ischemic Stroke
Venous Sinus Thrombosis
Intracerebral Hemorrhage
Subarachnoid Hemorrhage
Diseases Associated with Ischemic Strokes
Diseases Associated with Hemorrhagic Strokes
Novel Anticoagulant Agents
References
Chapter 23: Hepatology
Introduction
Pathophysiology of Coagulopathy
Clinical manifestations of Liver Disease Coagulopathy
Progression of Fibrosis due to Parenchymal Extinction
Extracorporeal Circuits
Laboratory Investigation of Hemostasis in Liver Disease
Emerging Evidence for Rebalanced Coagulation in Liver Disease
Invasive Procedures and Liver Disease
References
Chapter 24: Nephrology
Bleeding in Renal Disease
Kidney Biopsy
Chronic Kidney Disease and Thrombosis
Thrombosis in Nephrotic Syndrome
ANCA Vasculitis and Venous Thromboembolism
Renal Vein Thrombosis
Renal Transplant and Thrombosis
Anticoagulant Use in Kidney Disease
Acknowledgment
References
Chapter 25: Oncology
Introduction
Clinical Aspects: Thrombosis and Bleeding
Occult Malignancy
The hypercoagulable State of Patients with Malignancy
Pathogenic Mechanisms
Prevention and Treatment of Thrombosis and Bleeding in Cancer
Anticoagulation and Cancer Survival
References
Chapter 26: Obstetrics, Contraception, and Estrogen Replacement
Physiological Changes in Pregnancy
Venous Thromboembolism
Prevention of Gestational VTE
Diagnosis of Acute VTE
Treatment of Acute VTE
Post-Thrombotic Syndrome
Warfarin in Pregnancy
Management of Delivery on Full Anticoagulation
Obstetric Antiphospholipid Syndrome
Contraception, HRT, and
in Vitro
Fertilization
References
Chapter 27: Pediatrics
Quaternary Care Pediatrics: Trading One Problem for Another
Hemostasis in Children
Indications for Anticoagulation
Diagnosis of Thrombosis in Children
Epidemiology of Thrombosis in Children
Outcomes of Thrombosis in Children
Therapeutic Agents and Metabolism
Antithrombotic Therapy in Children
Thrombophilia Testing in Children
Difficulties in Performing Clinical Trials in Children
Future Perspectives
References
Chapter 28: Intensive and Critical Care
Introduction
Managing Coagulopathies in Critical Care
Thrombocytopenia
Patients with Sepsis
Thresholds for Platelet Transfusion
The Thrombotic Microangiopathies
Sepsis and the Systemic Inflammatory Response Syndrome (SIRS)
Sequential Organ Failure Assessment Score
Heparin Induced Thrombocytopenia
Thrombocytosis
Management of Thromboembolism in ICU
Thromboprophylaxis in the ICU
Special Situations in Critical Care
References
Chapter 29: Transfusion
Introduction
Blood Transfusion as a Form of Transplantation
Risks of Transfusion
Transfusion Reactions
Blood Products Available
Drugs that Reduce the Need for Transfusion
Use of Blood Products
Special Situations
Hemovigilance and Regulation of Transfusion
Conclusions
Web Sites of Interest
References
Appendix 1: Reference Ranges
Background
Selection of Subjects
Number of Subjects Required
Processing of Samples
Change in Reagent Lot Numbers
Data Analysis
Examples of Locally Determined Reference Ranges
Pregnancy Normal Ranges
Neonatal Normal Ranges
Conclusion
References
Index
End User License Agreement
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Guide
Table of Contents
Begin Reading
List of Illustrations
Chapter 1: Basic Principles Underlying Coagulation
Figure 1.1
Vessel
. An intact blood vessels is pictured with the endothelial cells (tan) and surrounding pericytes (dark brown). Within the vessel are red blood cells and platelets (blue). Associated with the pericytes, tissue factor complexed with factor VII(a) is shown in green. Factor IX, shown in blue, is associated with collagen IV in the extravascular space. .
Figure 1.2
Initiation
. A break in the vasculature brings plasma coagulation factors and platelets into contact with the extravascular space. Unactivated platelets within the vessel are shown as blue disks. Platelets adhering to collagen in the extravascular space are activated and are represented as blue star shapes to indicate cytoskeletal-induced shape change. The expanded view shows the protein reactions in the initiation phase. Factor VIIa–tissue factor activates both factor IX and factor X. Factor Xa, in complex with factor Va released from platelets, can activate a small amount of thrombin (IIa). .
Figure 1.3
Amplification
. Platelets, shown as blue discs, aggregate to stop blood loss from the break in the vasculature. Activated platelets are shown as star shapes. The expanded view shows thrombin (red) generated during the initiation phase binding to the glycoprotein Ib–IX–V complex (GP Ib–IX–V) on platelets. When bound, thrombin is somewhat protected from inhibition and can cleave protease activated receptor (PAR) 1 at the recognition site (black sphere). When the new amino terminal folds back on the seven transmembrane domain, a signaling cascade is initiated leading to surface exposure of phosphatidylserine as well as degranulation of alpha (white circle) or dense (not shown) granules. Factor Va is released from alpha granules and further activated by thrombin. Also, factor VIII is activated by cleavage and release from von Willebrand factor (vWF). .
Figure 1.4
Propagation
. The expanded view shows platelet surface thrombin generation. Factor IXa, formed during the initiation phase, can move into a complex with factor VIIIa formed during the amplification phase. This IXa–VIIIa complex cleaves factor X. Factor Xa, in complex with platelet surface factor Va, generates a burst of thrombin (IIa). This thrombin can feed back and activate platelet surface bound factor XI; the resulting factor XIa can feed more factor IXa into the reaction. This additional factor IXa enhances factor Xa and thrombin generation. As shown in the overview, the burst of thrombin stabilizes the initial platelet plug as all of the platelets are now activated (represented as blue star shapes as opposed to the disc shaped platelets in circulation). The factor VIIa–tissue factor complex with associated factor Xa is inhibited by TFPI. .
Figure 1.5
Localization
. Thrombin generated during the propagation phase cleaves fibrinopeptides A and B leading to fibrin assembly (shown as brown distributed among and associated with the blue star shapes that represent activated platelets). The result is a stable platelet plug with fibrin and bound thrombin distributed throughout the plug. The expanded view shows the interface between the platelet plug (blue) and healthy endothelium. Thrombin released into the circulation is inhibited by antithrombin (AT) to form a thrombin–antithrombin complex (TAT). Also, thrombin (IIa) that reaches the endothelial cell surface binds tightly to thrombomodulin (TM). The thrombin–thrombomodulin complex activates protein C (PC) in a reaction enhanced by the endothelial cell protein C receptor (EPCR). Activated protein C (APC) in a reaction enhanced by protein S (PS) can cleave factor Va to inactivated factor Va (iVa). So thrombin on healthy endothelium participates in a negative feedback process that prevents thrombin generation away from the platelet plug that seals an injury. .
Chapter 2: Laboratory Tests of Hemostasis
Figure 2.1 Investigation of a prolonged prothrombin time (PT). APTT, activated partial thromboplastin time.
Figure 2.2 Investigation of a prolonged activated partial thromboplastin time (APTT). DRVVT, dilute Russell viper venom time.
Figure 2.3 Investigation of a prolonged thrombin time. FDP, fibrin(ogen) degradation products.
Chapter 3: Molecular Diagnostic Approaches to Hemostasis
Figure 3.1 The
F8
gene and the two additional transcripts originating from the
F8
locus (
F8A
and
F8B
).
Figure 3.2 Molecular genetic testing algorithm for severe hemophilia A.
Figure 3.3 Sequencing chromatogram from a severe hemophilia A patient. In this woman, the
F8
mutation is a single adenine insertion into a run of eight adenine residues in exon 14. The “A” insertion results in a reading frameshift.
Figure 3.4 A Southern blot autoradiograph of the intron 22 inversion mutation in
F8
, the cause of ~45% of the cases of severe hemophilia A. N, normal; H, hemophilia A due to the inversion mutation; and C, carrier female for the intron 22 inversion.
Figure 3.5 The
VWF
gene with an indication of the region of the gene (exons 23–34) that is duplicated on chromosome 22 in a partial
VWF
pseudogene.
Figure 3.6 Diagram of the VWF protein (propolypeptide and mature subunit) with localization of the molecular defects responsible for type 2 von Willebrand disease (VWD).
Figure 3.7 Molecular genetic testing approaches for thrombophilic traits.
Chapter 4: Tests of Platelet Function
Figure 4.1 Platelet structure and organelles. This diagram summarizes the key structural elements of a platelet, including the open canalicular system (OCS), the dense tubular system, action microfilaments and microtubules, mitochondria, glycogen stores, dense granules, lysosomes, and alpha granules. ADP, adenosine diphosphate; ATP, adenosine triphosphate; PDGF, platelet derived growth factor; SDF, stromal cell derived factor; TGF, transforming growth factor; VWF, von Willebrand factor.
Figure 4.2 Platelet adhesion, activation, and aggregation. (a) Normal endothelium releases antiaggregant molecules promoting hemostasis and nonthrombogenic state. (b) Injured endothelium exposes platelets to thrombogenic subendothelium. Activated platelets release proaggregant molecules. (c) Clot formation at site of injury. Endothelium releases factors that stabilize the clot and limit the haemostatic process to the site of injury. ADP, adenosine diphosphate; NO, nitric oxide; PGI
2
, prostacyclin; t-PA, tissue plasminogen activator; TxA
2
, thromboxane A
2
.
Figure 4.3 Example lumiaggregometry traces from a patient with an ADP P2Y
12
receptor mutation and from a healthy volunteer (control). The agonist used in this trace was a very high concentration of adenosine diphosphate (ADP) (100 μM). Control aggregation is shown in blue, patient aggregation is shown in red. Control adenosine triphosphate (ATP) secretion is shown in black, patient ATP secretion is shown in green. Secondary wave of aggregation is seen in the healthy volunteer and is labeled, whereas the patient shows no ATP secretion and no secondary wave of aggregation, with deaggregation noted after initial primary wave formation. Addition of the ATP standard to allow calculation of secretion to normalized platelet count is also labeled. .
Figure 4.4 Electron microscopy imaging. (a) Transmission electron microscopy (TEM) of a normal platelet. Ultrathin sections (70–90 nm thick) stained with uranyl acetate and lead citrate revealing the different granule populations. M, mitochondria; α, alpha granule; δ, dense granule; OCS, open canalicular system. Scale bar 1 µm. (b) Whole mount electron micrograph of a normal platelet. Platelet-rich plasma was applied directly onto the EM grid and imaged. The dense granules (black arrows) contain calcium, which blocks the electron beam, therefore they appear as black dots. Scale bar 1 µm.
Figure 4.5 A flow cytometry plot using a fluorescent-labeled platelet-identifying antibody (anti-CD61) when triggering on a low value of forward scatter. If the instrument is triggered on this fluorescence, all other nonplatelet events shown (RBCs) will be eliminated from the analysis. Optimization of dilution will also eliminate the coincident events.
Figure 4.6 A typical flow cytometry protocol for the testing and analysis of platelets. Small amounts of blood are incubated with test reagents, diluted, and analyzed. New reagents are easily incorporated into this standard procedure.
Chapter 5: Evaluation of the Bleeding Patient
Figure 5.1 Diagnostic evaluation for patient with elevated prothrombin time (PT) and normal activated partial thromboplastin time (APTT). DIC, disseminated intravascular coagulation.
Figure 5.2 Diagnostic algorithm for patient with normal prothrombin time (PT) and prolonged activated partial thromboplastin time (APTT). HMWK, high molecular weight kininogen; LA, lupus anticoagulant; PK, prekallikrein; RT, reptilase time; TCT, thrombin clotting time; VWD, von Willebrand disease.
Figure 5.3 Diagnostic evaluation for patient with prolongations of both prothrombin time (PT) and activated partial thromboplastin time (APTT). DIC, disseminated intravascular coagulation; TCT, thrombin clotting time.
Chapter 6: Hemophilia A and B
Figure 6.1 Right knee hemarthrosis in a severe hemophilia A patient. Bleeds such as this are unusual in countries where patients have home treatment with clotting factor concentrates. Usually the there are no physical signs and the only symptoms are pain and limitation of joint movement.
See Plate section for color representation of this figure.
Figure 6.2 Fatal spontaneous cerebral bleed in a hemophilia B patient.
Figure 6.3 Extensive spontaneous subcutaneous hematoma in a patient with acquired hemophilia A. In contrast to congenital hemophilia, these patients often present with extensive subcutaneous bleeds and rarely have hemarthroses.
See Plate section for color representation of this figure.
Chapter 7: Von Willebrand Disease
Figure 7.1 Flow-chart of a practical approach to the treatment of von Willebrand disease. Platelet count drops in type 2B after desmopressin; exclusion of type 2B with RIPA desirable. *Urine output and serum electrolytes control; caution in young children.
Chapter 9: Acquired Inhibitors of Coagulation
Figure 9.1 Age-related incidence of acquired hemophilia A. Data are shown for the percentage of patients presenting with acquired hemophilia A in each decade of life in two large cohorts, a treatment study and a combined analysis of 20 cohorts.
Source:
data from Green and Lechner 1981, Collins
et al
. 2007 [3, 6]; Morrison
et al
. 1993, Delgado
et al
. 2003 [5, 7]; and EACH2 registry Levesque
et al
. 2009 [8].
Figure 9.2 Patient presenting with acquired hemophilia having typical large soft tissue bleeds, after sleeping on his left side and exerting his left arm. The photograph is from the time of diagnosis, which was delayed for several days.
Source:
With permission from Duodecim Medical Journal, Finland, 2003.
See Plate section for color representation of this Figure See also Figure 6.3, page 91.
Chapter 10: Quantitative Platelet Disorders
Figure 10.1 Diagnostic strategy for evaluating thrombocytopenia. DIC, disseminated intravascular coagulation; HUS, hemolytic uremic syndrome; ITP, immune thrombocytopenia; TTP, thrombotic thrombocytopenic purpura.
Figure 10.2 Peripheral blood smear in a patient with microangiopathic hemolytic anemia showing helmet cells, schistocytes, and microspherocytes.
Source
: Kumar
et al
. 2013 [47]. Reproduced with permission of Karger Medical and Scientific Publishers. .
Figure 10.3 (a) Peripheral blood smear from a patient with MYH9-RD demonstrating giant platelet (arrow) and neutrophil inclusion (arrowhead). Immunofluorescent visualization of nonmuscle myosin heavy chain IIA aggregates: (b) normal homogenous cytoplasmic staining (lower left) and (c) abnormal variable speckled cytoplasmic staining. .
Figure 10.4 (a) Peripheral blood smear from a patient with gray platelet syndrome demonstrating large gray-appearing platelets. (b) Platelet transmission electron micrograph from a patient with gray platelet syndrome showing complete absence of alpha granules with increased vacuoles. Scale bar represents 5 nanometers.
Source
: Kumar and Kahr 2013 [12]. Reproduced with permission of Elsevier. .
Chapter 12: Disseminated Intravascular Coagulation
Figure 12.1 Pathogenesis of DIC.
Figure 12.2 Purpura fulminans in a patient with meningococcemia. Purpura fulminans is associated with underlying DIC and is characterized by widespread ecchymosis and ischemic infarction of the skin.
Chapter 13: Thrombotic Microangiopathies
Figure 13.1 The role of ADAMTS13 in the pathophysiology of thrombotic thrombocytopenic purpura (TTP). VWF, von Willebrand factor.
Figure 13.2 The role of complement in the pathophysiology of atypical hemolytic uremic syndrome.
Chapter 14: Venous Thromboembolism
Figure 14.1 Acute right lower extremity deep vein thrombosis. Note the swelling, erythema, and pitting edema.
Figure 14.2 Post-thrombotic syndrome. Although usually the symptoms are confined to itching, mild swelling and pain, when severe there is pigmentation and ulceration over the medial malleolus.
Figure 14.3 Pulmonary embolus in the pulmonary artery causing sudden death in a young woman who was using the combined pill.
Source:
Makris and Greaves, 1997 [4].
Figure 14.4 Pulmonary angiogram showing massive pulmonary embolism in the right pulmonary artery.
Figure 14.5 Diagnostic algorithm for PE. *Choice of additional diagnostic testing depends on clinical presentation and local expertise. CTPA, computerized tomographic pulmonary angiography (multidetector); US, ultrasound; V/Q, ventilation–perfusion; angio, angiography; ILFD, intraluminal filling defect.
Figure 14.6 Prominent superficial venous collaterals in a patient with inferior vena caval (IVC) thrombotic occlusion, occurring as a late complication of an IVC filter.
Chapter 15: Myeloproliferative Neoplasms: Thrombosis and Hemorrhage
Figure 15.1 The diagnostic algorithm for the classic
BCR-ABL
-negative myeloproliferative neoplasms (MPNs) begins with peripheral blood
JAK2
V617F mutation testing, as the test has a good sensitivity and specificity for these diseases. A bone marrow biopsy should be considered in all patients both for diagnosis and prognosis.
a
The
JAK2
V617F mutation test is augmented by serum erythropoietin (EPO) testing in polycythemia vera (PV), as approximately 5% of PV patients will lack the mutation.
b
A further 3% of PV patients will have a mutation in the
JAK2
exon 12 and essentially all of these will have a low serum EPO level [35].
c
Though an MPN is confirmed, a bone marrow biopsy is needed to distinguish between ET and prefibrotic primary myelofibrosis (PMF).
d
If clinical suspicion for PV remains high despite negative
JAK2
mutation testing,
CALR
mutation testing should be done. If mutation testing is negative, a bone marrow biopsy to evaluate for erythroid hyperplasia and bizarre megakaryocyte clusters is indicated.
e
Bone marrow biopsy needed for diagnostic and prognostic purposes.
Figure 15.2 Tailored treatment for essential thrombocythemia (ET). A proposed algorithm for the treatment of ET incorporates
JAK2
V617F mutation status and the presence of cardiovascular risk factors to tailor therapy. Twice-daily aspirin may be considered in some cases, as there may be incomplete platelet inhibition by aspirin due to increased platelet turnover. CVR, cardiovascular risk factors.
Chapter 16: Arterial Thrombosis
Figure 16.1 Choice of antithrombotic therapy in patients with atrial fibrillation. Antiplatelet therapy with aspirin plus clopidogrel, or less effectively aspirin only, should be considered in patients who refuse any oral anticoagulant, or cannot tolerate anticoagulants for reasons unrelated to bleeding. If there are contraindications to VKA, NOAC or antiplatelet therapy, left atrial appendage occlusion, closure or excision may be considered.
a
Includes rheumatic valvular disease and prosthetic valves. AF, atrial fibrillation; NOAC, novel oral anticoagulant; VKA, vitamin K antagonist. Solid line, best option; dashed line, alternative option.
Chapter 17: Anticoagulation: Heparins and Vitamin K Antagonists
Figure 17.1 Skin necrosis of the elbow in a patient who just started warfarin.
Figure 17.2 Subdural hematoma in a patient on warfarin.
Chapter 18: The Direct Oral Anticoagulants
Figure 18.1 Scheme for secondary venous thromboembolism (VTE) prevention (extended treatment) studies. R, randomization.
Chapter 20: Cardiovascular Medicine
Figure 20.1 Mechanism of action of antiplatelet agents in acute coronary syndromes. ADP, adenosine diphosphate; TXA
2,
thromboxane, ASA, aspirin.
Figure 20.2 Photograph and diagram of HeartMate II device.
Figure 20.3 Algorithm for the evaluation and treatment of gastrointestinal (GI) tract bleeding (the Duke approach). In the event that a patient supported with an axial-flow device develops GI tract bleeding, consultation from a GI specialist is of benefit to identify the bleeding source through endoscopy or use of the PillCam device. Initially, antiplatelet medication should be discontinued and bleeding should be reassessed. If bleeding continues, warfarin should be discontinued. Once the patient is hemodynamically stable, a target international normalized ratio (INR) of 1.5 to 2.0 is recommended. The medical team should consider alternative therapies to stop bleeding, including cryoprecipitate, platelets, factor VIII, octreotide, and desmopressin (DDAVP) in the event of uncontrolled hemorrhage. *There are no data indicating that endoscopy or the PillCam are beneficial in management of GI bleeding early after left ventricular assist device (LVAD) implantation when pre-LAVD endoscopy showed no bleeding source.
Chapter 21: Cardiothoracic Surgery
Figure 21.1 Cardiopulmonary bypass circuit.
Figure 21.2 The thrombelastogram profile compared with the clotting profile. MA, maximum amplitude; PT, prothrombin time; PTT, partial thromboplastin time.
Figure 21.3 The Wessex allogenic blood transfusion protocol. FFP, fresh frozen plasma; MA, maximum amplitude; TEG, thrombelastography.
Figure 21.4 Type of product transfused. Total number of units transfused by group in the operating room (OR) and intensive care unit (ICU). FFP, fresh frozen plasma; RBC, red blood cell.
Figure 21.5 Reduction in coagulation proteins in coronary artery bypass grafting. CPB, cardiopulmonary bypass.
Chapter 22: Neurology
Figure 22.1 A sagittal three-dimensional time-of-flight magnetic resonance venography was obtained in this patient presenting with headache and altered mental status. The superior sagittal sinus is absent due to thrombosis (arrows).
Figure 22.2 (a) This axial computed tomography image demonstrates a large left parietal–occipital parenchymal hemorrhage in a patient with amyloid angiopathy, which extended into the left lateral ventricle and resulted in the patient's death. (b) An axial T1 noncontrasted image in another patient with amyloid angiopathy demonstrates a mirror image parenchymal hemorrhage with surrounding vasogenic edema (arrow).
Figure 22.3 Sickle cell can lead to vascular occlusion as seen in this sickle cell patient who has total or near total occlusion of the right supraclinoid internal carotid artery, and M1 segment of the middle cerebral artery with possible reconstitution via the middle meningeal artery. This disease can progress further to a “moya moya” pattern and strokes without transfusion therapy.
Chapter 25: Oncology
Figure 25.1 Thrombotic disorders associated with cancer. Clinical manifestations of thrombosis in patients with cancer can vary from localized deep venous thrombosis, more frequent in solid tumors, to systemic syndrome, such as disseminated intravascular coagulation (DIC) with consumption of coagulation factors and platelets, which is generally associated to leukemias or widespread metastatic cancer.
Figure 25.2 Risk factors for cancer-associated thrombosis. Several clinical and biological factors can contribute to thrombotic risk in cancer patients, these include their demographic characteristics, site and stage of cancer, anti-cancer therapies (including surgery), hospitalization and biomarkers. VTE, venous thromboembolism.
Figure 25.3 Mechanisms for activation of blood coagulation and thrombotic diathesis in patients with cancer. Even in the absence of overt clinical symptoms, almost all patients present with laboratory coagulation abnormalities, demonstrating a subclinical activation of blood coagulation, which characterizes a “hypercoagulable state.” Multiple factors (i.e., general, tumor-specific and antitumor therapy-related) concur to the activation of blood coagulation and to thrombotic manifestation in cancer patients.
Figure 25.4 Experimental and clinical studies with molecularly well-defined types of cancer cells reveal how oncogenic events may deregulate the hemostatic system. Activated oncogenes (K-ras, EGFR, PML-RARa, and MET) or inactivated tumor suppressors (p53 or PTEN) lead to an induction of procoagulant activity and inhibition of fibrinolysis, which is postulated to promote not only hypercoagulability but tumor aggressiveness and angiogenesis.
Figure 25.5 Antitumor therapy prothrombotic mechanisms. Tumor cells perturbed by antitumor drugs release a series of soluble mediators (proinflammatoy and proangiogenic cytokines, proteolytic enzymes), which can act on endothelial cells by altering their normal antithrombotic and antiadhesive status or by damaging the endothelial monolayer, with the subsequent exposure of the highly procoagulant endothelial cell matrix. The same antitumor drugs can upregulate the expression of adhesion molecules by tumor cells which become much adhesive towards the endothelium.
Chapter 26: Obstetrics, Contraception, and Estrogen Replacement
Figure 26.1 Physiological changes in pregnancy.
Figure 26.2 Diagram of iliac vessels. .
Figure 26.3 A diagnostic algorithm for the investigation of suspected venous thromboembolism. *Yield is low but may be undertaken in some centers to reduce need for imaging. CTPA, computed tomography pulmonary angiogram; CXR, chest X-ray; DVT, deep vein thrombosis; LMWH, low molecular weight heparin; MR, magnetic resonance; PE, pulmonary embolism; USS, ultrasound scan; VTE, venous thromboembolism.
Chapter 27: Pediatrics
Figure 27.1 Receptor sites for antiplatelet agents. .
Chapter 28: Intensive and Critical Care
Figure 28.1 A local management protocol for heparin-induced thrombocytopenia (HIT). APTT, activated partial thromboplastin time; CTPA, computed tomographic pulmonary angiography; eGFR, estimated glomerular filtration rate; ELISA, enzyme-linked immunosorbent assay. .
Figure 28.2 A local management algorithm for managing massive pulmonary embolism (PE). CTPA, computed tomographic pulmonary angiography; IVC, inferior vena cava. .
Chapter 29: Transfusion
Figure 29.1 Choice of red cells by ABO group.
Figure 29.2 Post-transfusion purpura presenting with ecchymosis in a female patient with a platelet count of 10 × 10
9
/L, subsequently shown to be HPA-1a negative with anti-HPA-1a antibodies. Transfusion had been given preoperatively.
List of Tables
Chapter 2: Laboratory Tests of Hemostasis
Table 2.1 The volume of anticoagulant required for a 5-mL sample.
Table 2.2 Interpretation of abnormalities of coagulation screening tests.
Table 2.3 Conditions associated with a prolonged activated partial prothrombin time but without a bleeding diathesis.
Table 2.4 Effects of direct oral anticoagulants on tests of hemostasis.
Table 2.5 Expected plasma concentrations of direct oral anticoagulants (DOACs).
Chapter 4: Tests of Platelet Function
Table 4.1 Major platelet agonists and their surface receptors. Platelets express a remarkable number and variety of receptors for a wide range of ligands. For many of these receptor–ligand combinations, however, the effect on platelet activation is weak and of uncertain significance.
Table 4.2 Brief reference guide on inherited platelet disorders.
Table 4.3 Typical lumiaggregometry findings in commonly encountered platelet defects.
Table 4.4 Flow cytometric platelet function tests.
Chapter 6: Hemophilia A and B
Table 6.1 Classification of severity of hemophilia.
Table 6.2 Joints most frequently affected by spontaneous bleeds in severe hemophilia.
Table 6.3 Currently available clotting factor concentrates.
Table 6.4 Viral inactivation and removal techniques.
Table 6.5 Complications of clotting factor therapy.
Chapter 7: Von Willebrand Disease
Table 7.1 Recommended nomenclature of factor VIII/ von Willebrand factor complex.
Table 7.2 Classification of von Willebrand disease.
Table 7.3 Type 1 von Willebrand disease: heterogeneity of clinical and laboratory phenotype.
Table 7.4 Practical approach to the diagnosis of von Willebrand disease (VWD).
Table 7.5 Grades of bleeding severity used to compute the bleeding score in the ISTH Consensus Bleeding Assessment Tool.
Table 6 Basic and discriminating laboratory assays for the diagnosis of von Willebrand disease.
Table 7 Other tests proposed for von Willebrand disease diagnosis.
Table 7.8 Doses of FVIII–VWF concentrates recommended in von Willebrand disease patients unresponsive to desmopressin.
Chapter 8: The Rarer Inherited Coagulation Disorders
Table 8.1 Prevalence and chromosomal location of affected gene in the rare inherited coagulation disorders.
Chapter 9: Acquired Inhibitors of Coagulation
Table 9.1 Underlying conditions in acquired hemophilia.
Table 9.2 Laboratory findings and differential diagnosis for acquired hemophilia, AVWS and other acquired coagulation inhibitors.
Table 9.3 Rates of control for the first bleeding episodes by first-line therapy.
Chapter 10: Quantitative Platelet Disorders
Table 10.1 Causes of thrombocytopenia in children and adults.
Table 10.3 Drugs causing thrombocytopenia.
Table 10.2 Congenital thrombocytopenias characterized according to inheritance pattern, genetic mutations and associated findings.
Table 10.4 Causes of thrombocytopenia in newborns.
Chapter 11: Qualitative Platelet Disorders
Table 11.1 Congenital platelet defects.
Table 11.2 Acquired platelet defects.
Table 11.3 Drugs affecting platelet function.
Chapter 12: Disseminated Intravascular Coagulation
Table 12.1 Conditions associated with disseminated intravascular coagulation (DIC).
Table 12.2 Diagnostic scoring system for overt disseminated intravascular coagulation (DIC). Do not use this algorithm unless the patient has an underlying disorder that is associated with DIC.
Table 12.3 Diagnostic scoring system for nonovert DIC. Score of 0, 1, or 2 is assigned for criteria plus a score for rising, stable, or falling.
Table 12.4 The Japanese Association for Acute Medicine disseminated intravascular coagulation (DIC) score.
Chapter 13: Thrombotic Microangiopathies
Table 13.1 Differential diagnosis of thrombotic microangiopathies.
Chapter 14: Venous Thromboembolism
Table 14.1 Risk factors for venous thromboembolism (VTE).
Table 14.2 Natural history of venous thromboembolism (VTE).
Table 14.3 Test results that confirm or exclude deep vein thrombosis (DVT).
Table 14.4 Wells’ model for determining clinical suspicion of deep vein thrombosis (DVT).
Table 14.5 Test results that confirm or exclude pulmonary embolism (PE).
Table 14.6 Wells’ model for determining clinical suspicion of pulmonary embolism (PE).
Chapter 15: Myeloproliferative Neoplasms: Thrombosis and Hemorrhage
Table 15.1 Comparison of classic (
BCR-ABL
-negative) myeloproliferative neoplasms.
Table 15.2 World Health Organization (WHO) 2016 Diagnostic Criteria for the
BCR-ABL
negative myeloproliferative neoplasms [2].
Table 15.3 Patients with unexplained thrombosis – whom to test for an occult myeloproliferative neoplasm (MPN)?
Table 15.4 Management of polycythemia vera (PV) and essential thrombocythemia (ET).
Table 15.5 Drugs used in the treatment of
BCR-ABL-
negative myeloproliferative neoplasms (MPNs).
Table 15.6 Pregnancy management in myeloproliferative disorders – considerations.
a
Chapter 16: Arterial Thrombosis
Table 16.1 Risk factors for cardiovascular disease [2, 47, 48].
Table 16.2 Summary of lifestyle advice and pharmacological prevention of cardiovascular disease [50, 51].
Table 16.3 CHA
2
DS
2
-VASc risk stratification index for patients with nonvalvular atrial fibrillation [6, 52].
Table 4 Stroke risk according to CHA
2
DS
2
-VASc score – Danish data from 73 538 hospitalized patients with atrial fibrillation who were not treated with vitamin K antagonists.
Table 16.5 Summary of laboratory tests in persons with arterial thromboembolism.
Chapter 17: Anticoagulation: Heparins and Vitamin K Antagonists
Table 17.1 Indications and contraindications (absolute or relative) for anticoagulant treatment with vitamin K antagonists.
Table 17.2 Classification of bleeding complications.
Table 17.3 Strategies to manage patients treated with VKAs who require surgery or invasive procedures.
Chapter 18: The Direct Oral Anticoagulants
Table 18.1 Pharmacological properties of the direct oral anticoagulants.
Table 18.2 Potential drug–drug interactions within the target specific oral anticoagulants. Specific evidence of clinically important changes resulting in thrombosis or bleeding is lacking for almost all of these potential interactions. The reader should consult the prescribing package for updated information on clinically important interactions.
Table 18.3 Phase III randomized controlled trials comparing the novel oral anticoagulants versus conventional treatment after elective total hip replacement.
Table 18.4 Phase III randomized controlled trials comparing the novel oral anticoagulants versus conventional treatment after elective total knee replacement.
Table 18.5 Phase III randomized controlled trials comparing the novel oral anticoagulants versus standard of care for acute venous thromboembolism.
Table 18.6 Phase III randomized controlled trials comparing the novel oral anticoagulants versus placebo or warfarin for extended treatment of venous thromboembolism.
Table 18.7 Phase III randomized controlled trials comparing the novel oral anticoagulants versus warfarin for stroke prevention in atrial fibrillation patients.
Table 18.8 Clinical scenarios in which measurement of anticoagulant effect may be desired.
Table 18.9 Anticipated effect of direct oral anticoagulants on several laboratory assays. See also Cuker
et al
. 2014 [29]
Chapter 19: Antiphospholipid Syndrome
Table 19.1 Diagnostic criteria for antiphospholipid syndrome.
Table 19.2 Clinical features of antiphospholipid syndrome (APS), described by a cohort of 1000 European APS patients.
Table 19.3 Antigenic targets of antiphospholipid antibodies.
Table 19.4 Infections associated with antiphospholipid antibodies.
Chapter 20: Cardiovascular Medicine
Table 20.1 Fibrinolytic therapy recommendations.
Table 20.2 Agent-specific characteristics for oral anti-platelet drugs.
Table 20.3 Agent-specific characteristics for glycoprotein (GP)-IIB/IIIA receptor antagonists.
Table 20.4 Anticoagulants used in acute coronary syndromes.
Table 20.5 Agent-specific approach to hemorrhagic complications.
Chapter 21: Cardiothoracic Surgery
Table 21.1 Blood components received by the patients. The Table shows the number of patients (%) in each group that received transfusions.
Table 21.2 Results of study comparing blood-saving properties of antifibrinolytics.
Chapter 22: Neurology
Table 22.1 Strength of association of coagulopathy with arterial stroke.
Chapter 23: Hepatology
Table 23.1 Hemostatic defects in hepatic disease.
Table 23.3 Hypercoagulability and liver disease.
Table 23.4 Causes of Budd–Chiari syndrome.
Table 23.5 Laboratory abnormalities in liver disease.
Table 23.6 Coagulation abnormalities during liver transplantation.
Chapter 24: Nephrology
Table 24.1 Prevention and treatment of bleeding in patients with renal failure.
Table 24.2 Potential mechanisms of thrombophilia in the nephrotic syndrome.
Chapter 25: Oncology
Table 25.1 Circulating markers of hemostatic system activation.
Table 25.2 Tumor cell prothrombotic properties.
Table 25.3 Antitumor therapy prothrombotic mechanisms.
Table 25.4 Risk of venous thromboembolism in cancer patients undergoing surgery.
Table 25.5 Prolonged prophylaxis with low molecular weight heparin in surgical cancer patients.
Table 25.6 Randomized clinical trials testing the effect of low molecular weight heparin (LMWH) on survival in cancer patients.
Chapter 26: Obstetrics, Contraception, and Estrogen Replacement
Table 26.1 Risk factors for venous thromboembolism (VTE) in pregnancy (patient related and pregnancy specific).
Table 26.2 Prevalence of inherited thrombophilia and risk of gestational venous thromboembolism (VTE).
Table 26.3 Recommendations for thromboprophylaxis.
Table 26.4 Signs and symptoms of venous thromboembolism in pregnancy.
Table 26.5 Criteria for the diagnosis of antiphospholipid syndrome.
Table 26.6 Risk of venous thromboembolism associated with oral contraceptives.
Table 26.7 Risk of venous thromboembolism (VTE) associated with hormone replacement therapy (HRT).
Chapter 27: Pediatrics
Table 27.1 Coagulation inhibitor reference values for neonates and children.
Table 27.2 Summary of clinical properties of commonly used anticoagulants in children.
Table 27.3 Example of a unfractionated heparin (UFH) dosing nomogram using a therapeutic activated partial thromboplastin time (APTT) range of 60–85. Caution: Each institution will have a different therapeutic APTT range and the Table should be adjusted accordingly.
Table 27.4 Unfractionated heparin (UFH) reversal.
Table 27.5 Low-molecular-weight heparin (LMWH) dosing nomogram.
Table 27.6 Sample warfarin dosing nomogram: maintenance phase for target international normalized ratio (INR) 2.5 (2.0–3.0).
Chapter 28: Intensive and Critical Care
Table 28.1 Laboratory findings in various platelet and coagulation disorders in critical care.
Table 28.2 Differential diagnosis of thrombocytopenia in the ICU setting.
Table 28.3 The Sequential Organ Failure Assessment (SOFA) score.
Table 28.4 Suggested venous thromboembolism prophylaxis in critically ill patients.
Table 28.5 Possible additional risk factors for venous thromboembolism disease in renal transplant recipients.
Chapter 29: Transfusion
Table 29.1 Common red cell blood group systems.
Table 29.2 ABO antigen and antibodies.
Table 29.3 Examples of transfusion-transmitted infections.
Table 29.4 Causes of major hemorrhage in obstetrics.
Table 29.5 Acceptance of blood products by Jehovah's Witnesses.
Appendix 1: Reference Ranges
Table 1 Normal ranges in the authors' laboratory in 2014.
Table 2 Normal ranges in pregnancy.
Table 3 Normal ranges for neonates and children.
Practical Hemostasis and Thrombosis
Edited by Nigel S. Key, Michael Makris and David Lillicrap
Third Edition
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Library of Congress Cataloging-in-Publication Data
Names: Key, Nigel, 1956- editor. | Makris, Michael, editor. | Lillicrap, David, editor.
Title: Practical hemostasis and thrombosis / edited by Nigel S. Key, Michael Makris, David Lillicrap.
Description: Third edition. | Chichester, West Sussex ; Hoboken, NJ : John Wiley & Sons Inc., 2017. | Includes bibliographical references and index.
Identifiers: LCCN 2016036143| ISBN 9781118344712 (cloth) | ISBN 9781118344750 (epub) | ISBN 9781118344743 (Adobe PDF)
Subjects: | MESH: Hemostasis-physiology | Blood Coagulation Disorders | Hemorrhagic Disorders | Thrombosis | Thromboembolism
Classification: LCC RC647.C55 | NLM WH 310 | DDC 616.1/57-dc23
LC record available at https://lccn.loc.gov/2016036143
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Cover image: Science Photo Library - STEVE GSCHMEISSNER/Gettyimages
List of Contributors
Walter Ageno, MD
University of Insubria
Varese
Italy
Elina Armstrong, MD
Coagulation Disorders Unit, Department of Hematology, Comprehensive Cancer Center
Helsinki University Hospital
Helsinki
Finland
Roopen Arya, MA PhD FRCP FRCPath
Thrombosis and Haemostasis
Department of Haematological Medicine
King's College Hosptial
London
UK
Natalie Aucutt-Walter, MD
Division of Vascular Neurology
Department of Neurology
Penn State Milton S. Hershey Medical Center
Hershey, PA
Catherine N. Bagot, MBBS MD FRCPath
Department of Haematology
Royal Infirmary
Glasgow
UK
Mary Bauman, RN MN NP
Stollery Children’s Hospital
University of Alberta Edmonton
Canada
Richard C. Becker, MD
Division of Cardiovascular Health and Disease
University of Cincinnati College of Medicine
Cincinnati
Ohio
USA
Paula HB Bolton-Maggs, DM FRCP FRCPath
Serious Hazards of Transfusion Office
Manchester Blood Centre, Plymouth Grove
Manchester
UK
Aisha Bruce, MD
University of Alberta
Medical Director Pediatric Hematology
Stollery Children’s Hospital
Edmonton
Canada
G. Castaman, MD
Center for Bleeding Disorders and Coagulation
Department of oncology
Careggi University Hospital
Florence
Italy
Marco Cattaneo, MD
Medicina III, Ospedale San Paolo
ASST Santi Paolo e Carlo
Dipartimento di Scienze della Salute
Università degli Studi di Milano
Milano, Italy
Adrian Copplestone, MB BS
Plymouth University Peninsula School of Medicine
UK
B.Cosmi, MD PhD
Dept Angiology and Blood Coagulation
Department of Experimental, Diagnostic and Specialty Medicine
S.Orsola-Malpighi University Hospital
Bologna, Italy
Mark Crowther, BSc (Med Sci) MBChB MSc MRCP FRCPath
Department of Haematology
Worcestershire Royal Hospital
Worcester
England, UK
Mark A. Crowther
, MD
McMaster University
Hamilton
Canada
Vimal K. Derebail
, MD MPH
UNC Kidney Center
Division of Nephrology and Hypertension Department of Medicine
University of North Carolina
North Carolina, USA
Anna Falanga
, MD
Department Immunohematology and Transfusion Medicine
Hospital Papa Giovanni XXIII
Bergamo
Italy
Eti Alessandra Femia, PhD
Medicina 3, Ospedale San Paolo Dipartimento di Scienze della Salute
Università degli Studi di Milano
Milan
Italy
David A. Garcia,
MD
Medicine/Hematology
University of Washington Medical Center
Seattle
USA
Ravi Gill, BM
Southampton University Hospitals Trust Tremona Road
Southampton
UK
Dr. Paul Harrison, BSc PhD FRCPath
Healing Foundation
Institute of Inflammation and Ageing (IIA)
University of Birmingham Laboratories
New Queen Elizabeth Hospital
Birmingham
UK
David Y. Huang, MD PhD
UNC Health Care Comprehensive Stroke Center
Division of Stroke and Vascular Neurology
Department of Neurology
University of North Carolina
North Carolina
USA
Beverley J. Hunt, MB ChB FRCP FRCPath MD
Thrombosis & Haemostasis, King’s College
Departments of Haematology & Pathology Guy’s & St Thomas’ NHS Foundation Trust & Viapath
London, UK
Dr. Paula James, DM FRCP FRCPath
Department of Medicine
Queen’s University
Kingston
Canada
Valerie L. Jewells, DO FACR
Department of Radiology
University of North Carolina at Chapel Hill
Chapel Hill
North Carolina, USA
Walter H.A. Kahr
, MD PhD FRCPC
Departments of Pediatrics and Biochemistry University of Toronto
Division of Hematology/Oncology and Program in Cell Biology
The Hospital for Sick Children
Toronto
Canada
Raj S. Kasthuri, MB BS
Division of Hematology and Oncology
University of North Carolina
Chapel Hill
North Carolina, USA
David Kavanagh, MB ChB PhD
Institute of Genetic Medicine
Newcastle University
Newcastle upon Tyne
UK
Clive Kearon, MB MRCPI FRCPC PhD
Department of Medicine
Division of Hematology & Thromboembolism
McMaster University
Hamilton, Ontario
Canada
Nigel S. Key, MB ChB FRCP
Division of Hematology and Oncology
University of North Carolina
Chapel Hill, North Carolina
USA
Steve Kitchen, PhD
Sheffield Haemophilia and Thrombosis Centre
Royal Hallamshire Hospital
Sheffield
UK
Riten Kumar
, MD MSc
The Ohio State University
The Joan Fellowship in Pediatric Hemostasis-Thrombosis
Division of Hematology/Oncology/BMT
Nationwide Children’s Hospital
Columbus, USA
Sarah Takach Lapner, MD MSc FRCPC
Department of Medicine Division of Hematology
University of Alberta
Edmonton, Alberta
Canada
Riitta Lassila, MD PhD
University of Helsinki
Haemophilia Center
Department of Hematology
Comprehensive Cancer Center
Helsinki University Hospital
Helsinki
Finland
Dr. David Lillicrap, MD FRCPC
Department of Pathology and Molecular Medicine
Richardson Laboratory
Queen’s University
Kingston
Canada
Lori-Ann Linkins, MD MSc(Clin Epi) FRCPC
Department of Medicine
Division of Hematology & Thromboembolism
McMaster University
Hamilton, Ontario
Canada
Marie Lordkipanidzé, BPharm PhD
Université de Montréal & Research center
Montreal Heart Institute
Canada
Gillian C. Lowe, MRCP FRCPath PhD
University Hospital Birmingham NHS Foundation Trust and College of Medical and Dental Sciences
University of Birmingham
UK
Alice Ma, MD
University of North Carolina
Chapel Hill, North Carolina
USA
Rhona M. Maclean, MB ChB
Sheffield Haemophilia and Thrombosis Centre
Royal Hallamshire Hospital
Sheffield
UK
Mike Makris, MD
Sheffield Haemophilia and Thrombosis Centre
Royal Hallamshire Hospital
Sheffield
UK
Marina Marchetti, PhD
Department Immunohematology and Transfusion Medicine
Hospital Papa Giovanni XXIII
Bergamo
Italy
M. Patricia Massicotte, MD MSc
Director KIDCLOT Program
University of Alberta
Stollery Children’s Hospital
Edmonton
Canada
Marshall Mazepa, MD
Department of Pathology and Laboratory Medicine
University of North Carolina
Chapel Hill, North Carolina
USA
Stephan Moll, MD
University of North Carolina School of Medicine
Department of Medicine, Division of Hematology-Oncology
Chapel Hill, North Carolina
USA
Dougald M. Monroe, PhD
Division of Hematology/Oncology School of Medicine
University of North Carolina
North Carolina
USA
Denise O'Shaughnessy, DPhil
Southampton University Hospitals Trust
Tremona Road
Southampton
UK
Thomas L. Ortel,
MD PhD
Division of Hematology Department of Medicine
Duke University
North Carolina
USA
Gualtiero Palareti, MD
Cardiovascular Diseases
University of Bologna
Italy
Raj K. Patel, MD FRCP FRCPath
Department of Haematological Medicine
King's College Hospital
London
UK
Sue Pavord, MB ChB
Department of Haematology
Oxford University Hospitals NHS Foundation Trust
UK
Gillian N. Pike, BMedSci MBChB MRCP FRCPath
St. James’s University Hospital
Leeds
UK
Gian Marco Podda, PhD MD
Medicina 3, Ospedale San Paolo Dipartimento di Scienze della Salute
Università degli Studi di Milano
Milan
Italy
Brandi Reeves, MD
Division of Hematology and Oncology
University of North Carolina
Chapel Hill, North Carolina
USA
Lara N. Roberts, MD FRCP FRCPath
Consultant Haematologist
Department of Haematological Medicine
King's College Hospital
London
UK
Francesco Rodeghiero, MD
Hematology Unit
San Bortolo Hospital
Vicenza
Italy
Marie Scully, MD
University College of London Hospitals
London
UK
R. Campbell Tait, MBChB FRCP FRCPath
Department of Haematology
Royal Infirmary
Glasgow
UK
Alberto Tosetto, MD
Hemophilia and Thrombosis Center
Hematology Unit
San Bortolo Hospital
Vicenza
Italy
Sreekanth Vemulapalli
, MD
Division of Cardiology, Duke University School of Medicine
Duke Clinical Research Institute
Durham, North Carolina
USA
Michael J. Wang, MD
UNC Health Care Comprehensive Stroke Center
Division of Stroke and Vascular Neurology
Department of Neurology
University of North Carolina
North Carolina
USA
Henry G. Watson, MD FRCP FRCPath
Department of Haematology
Aberdeen Royal Infirmary
Aberdeen
Scotland
UK
Amy Webster, MB ChB
Department of Haematology
University Hospitals of Leicester
Leicester
UK
Jonathan Wilde, MB BChir
Department of Haematology
University Hospitals Birmingham NHS Foundation Trust
Queen Elizabeth Hospital, Queen Elizabeth Medical Centre
Birmingham
UK
Chapter 1Basic Principles Underlying Coagulation
Dougald M. Monroe
Key Points
This model of hemostasis views the process as having three overlapping phases: initiation, amplification, and propagation.
Initiation takes place on cells that contain tissue factor when factor VIIa/TF activates factors IX and X; the factor Xa generates a small amount of thrombin.
Thrombin from the initiation phase contributes to platelet activation and activates factors V and VIII.
Propagation takes place on the activated platelet when factor IXa from the initiation phase binds to platelet factor VIIIa leading to platelet surface factor Xa, which complexes with factor Va giving a burst of thrombin.
In clinical assays, the PT assess the initiation phase and the APTT assesses the propagation phase.
This chapter will discuss coagulation in the context of a hemostatic response to a break in the vasculature. Coagulation is the process that leads to fibrin formation; this process involves controlled interactions between protein coagulation factors. Hemostasis is coagulation that occurs in a physiological (as opposed to pathological) setting and results in sealing a break in the vasculature. This process has a number of components, including adhesion and activation of platelets coupled with ordered reactions of the protein coagulation factors. Hemostasis is essential to protect the integrity of the vasculature. Thrombosis is coagulation in a pathological (as opposed to physiological) setting that leads to localized intravascular clotting and potentially occlusion of a vessel. There is an overlap between the components involved in hemostasis and thrombosis, but there is also evidence to suggest that the processes of hemostasis and thrombosis have significant differences. There are also data to suggest that different vascular settings (arterial, venous, tumor microcirculation) may proceed to thrombosis by different mechanisms. Exploitation of these differences could lead to therapeutic agents that selectively target thrombosis without interfering significantly with hemostasis. Other chapters of this book will discuss some of the mechanisms behind thrombosis.
Healthy Vasculature
Intact vasculature has a number of active mechanisms to maintain coagulation in a quiescent state. Healthy endothelium expresses ecto-ADPase (CD39) and produces prostacyclin (PGI2) and nitric oxide (NO); all of these tend to block platelet adhesion to and activation by healthy endothelium [1]. Platelets in turn support a quiescent endothelium, in part through release of platelet granule components [2]. Healthy endothelium also has active anticoagulant mechanisms, some of which will be discussed below. There is evidence that the vasculature is not identical through all parts of the body [3]. Further, it appears that there can be alterations in the vasculature in response to changes in the extracellular environment. These changes can locally alter the ability of endothelium to maintain a quiescent state.
