Embed Size (px)
Citation preview
960 PART IV ■ THROMBOTIC DISORDERS
syndrome.28 A randomized study comparing LMWH with
aspirin in 58 patients with RVO showed better functional long-
term results with anticoagulation, but this result requires con-
fi rmation.29 Unusual sites of DVT are described in Chapter 84.
LONG-TERM CONSEQUENCES OF VENOUS
THROMBOEMBOLISM
Patients with DVT have a high risk of recurrence as well as
chronic venous insuffi ciency, the postthrombotic syndrome
(PTS) (FIGURE 80.4). The main cause of PTS is damage to the
delicate venous valves, with resulting refl ux and increased
venous pressure in the affected extremity. The clinical fi ndings
range from mild swelling in the evening, often combined with
symptoms of heaviness or tiredness in the leg, or skin discolor-
ations due to telangiectasia and malleolar fl are, to severe edema,
iron deposition with hyperpigmentation, lipodermatosclerosis,
and, ultimately, venous stasis ulcers30; the latter present in
5% of patients after 10 years.31 The Villalta score has been
recommended for quantifying the syndrome.32 Patients with
PE without symptomatic DVT also have an increased risk of
developing PTS, 41% at 10 years.31 Compression stockings
should be used to reduce the risk of PTS,33 but there are some
controversies. Once severe PTS has occurred, treatment is chal-
lenging. Some relief may be gained with intermittent pneumatic
compression,34 pentoxyphylline,35 or rutosides.36
Pulmonary hypertension (mean pulmonary artery pressure
≥25 mm Hg) is an incapacitating long-term sequel that has
been reported in 0.8% to 3.8% of patients 2 years after PE.37,38
It is unclear what transforms the original fragile emboli into
fi brotic, endothelialized obstructions that are tightly attached
to the arteries. The condition must be suspected when the
dyspnea persists or recurs without evidence of new emboli.
A screening program with echocardiography several years after
an episode of PE was not useful due to a low yield of only 0.57%
with chronic pulmonary hypertension.39 Right heart catheter-
ization is required to assess the pulmonary artery pressures
accurately, and central venous saturation and cardiac output
are needed to understand prognosis and decide on medical
therapy.40 Pulmonary endarterectomy is the treatment of choice
but should only be performed at highly specialized centers. The
long-term consequences of VTE are reviewed in Chapter 85.
PROPHYLAXIS OF VENOUS
THROMBOEMBOLISM
Prophylactic regimens against VTE have been most extensively
evaluated in major orthopedic surgery, notably hip or knee
replacements, with primary effi cacy being asymptomatic DVT
documented by venography and surgical wound bleeding serving
as a sensitive safety outcome. Recently, there has been intensive
debate around these outcomes. The value of asymptomatic
DVT as a surrogate outcome for fatal PE has been questioned.41
The European Medicines Agency has since 2007 recommended
a composite of (a) symptomatic or asymptomatic proximal
DVT, (b) symptomatic nonfatal PE, and (c) VTE-related death
or any death as the primary outcome;42 so asymptomatic distal
DVT may not be an acceptable surrogate outcome. Variations
in the defi nition of major bleeding have been used during the
past two decades,43 and attempts have been made to harmonize
this defi nition, published as recommendations by the Scientifi c
and Standardization Committee of the International Society
on Thrombosis and Haemostasis.44,45 The European Medicines
Agency refers to this defi nition in their recommendations.42,46
In major orthopedic surgery, prophylaxis against VTE is
today given to a high proportion of patients, although the rec-
ommended duration and start time are not followed for over
60% of patients.47 Overall compliance with guidelines in surgical
patients is 58.5%, and only 39.5% for medically ill patients,
according to the ENDORSE survey.48 Collins et al.49 showed in
a meta-analysis of more than 70 randomized trials that prophy-
laxis with low-dose unfractionated heparin (LDUH) reduces
fatal PE in the surgical setting from 0.81% to 0.26%. In the stud-
ies in medical patients, death was not signifi cantly affected.50,51
The duration of high VTE risk was recently addressed by the
EXCLAIM trial by evaluating extended prophylaxis with LMWH
in medically ill patients. Although prolongation of prophylaxis
to 28 days reduced the incidence of VTE, this occurred at the
cost of a signifi cant increase in major bleeding,52 a phenomenon
D-Dimer
Low Probability(unlikely)
Intermediate/HighProbability
(likely)
No Treatment
Imaging Diagnostics
Negative Positive
No Treatment
Negative Positive
Pulmonary Embolism? Deep Vein Thrombosis?
Clinical Assessment
History, Symptoms, Signs
FIGURE 80.3 Simplifi ed diagnostic algorithm for VTE.
Pulmonary EmbolismDeep Vein Thrombosis
ChronicThromboEmbolic
PulmonaryHypertension
Death
Postthrombotic Syndrome
TelangiectasiaVaricose VeinsLeg EdemaHyperpigmentation
Lipodermatosclerosis
Venous EczemaVenous Stasis Ulcers
Symptoms:TirednessPainVenous Claudication
FIGURE 80.4 Sequelae of VTE.
Marder_Chap80.indd 960
8/24/2012 4:10:34 PM
CHAPTER 123 ■ THROMBOHEMORRHAGIC COMPLICATIONS OF SEPSIS 1455
is extensive cross-talk between infl ammation and coagulation,41 and interestingly, systemic activation of coagulation and infl am-mation in sepsis can have some organ-specifi c manifestations.42
Initiation of Coagulation ActivationSystemic activation of coagulation in patients with sepsis has been considered to be a result of direct activation of the con-tact system by microorganisms or endotoxin.43 However, it has become apparent that the principal initiator of thrombin generation in sepsis is tissue factor (TF), without signifi cant change in markers refl ecting activation of the contact sys-tem.44,45 Furthermore, abrogation of the TF/factor VII(a) path-way by monoclonal antibodies completely inhibits thrombin generation in endotoxin-challenged chimpanzees and pre-vents DIC and mortality in baboons that are infused with Escherichia coli33,46,47
TF is a transmembrane 45 kDa protein, that is constitu-tively expressed on a number of cells throughout the body.48 The majority of these cells are in tissues not in direct contact with blood, such as the adventitial layer of large blood vessels. However, TF gets into contact with blood upon disruption of the vascular integrity, or if cells present in the circulation are altered to express TF. In sepsis, circulating mononuclear cells, stimulated by proinfl ammatory cytokines, express TF, but other than in severe meningococcemia,49 it is diffi cult to demonstrate ex vivo TF expression on monocytes of septic patients or experi-mental animals. However, low dose endotoxemia in healthy subjects results in a 125-fold increase in monocyte TF mRNA levels.50 Another source of TF may be on polymorphonuclear cells,51 although it is unlikely that these cells actually synthesize
TF in substantial quantities.52 Based on the transfer of TF from leukocytes to activated platelets in an ex vivo perfusion system, it is hypothesized that this “blood borne” TF is transferred between cells through microparticles derived from activated mononuclear cells.53
Platelets play a pivotal role in the pathogenesis of coagula-tion abnormalities in sepsis. Platelets can be activated directly by proinfl ammatory mediators, such as platelet activating factor.54 Once thrombin forms, additional platelets are activated, which then accelerates further fi brin formation. The expression of P-selectin on the platelet membrane not only mediates the adherence of platelets to leukocytes and endothelial cells but also enhances the expression of TF on monocytes by nuclear factor kappa-B (NFkB) activation.55 P-selectin is shed from the platelet membrane and soluble P-selectin levels are increased during systemic infl ammation.55
Impairment of the Antithrombin, Protein C, and TFPI Anticoagulant Pathways in SepsisActivation of coagulation is regulated by three major antico-agulant pathways, namely, AT3, the protein C system, and TF pathway inhibitor (TFPI). During sepsis-induced activation of coagulation, the function of all three pathways can be impaired (FIGURE 123.2).AT3 is a serine protease inhibitor and the main inhibitor of thrombin and factor Xa. During severe infl ammatory responses, AT3 levels are markedly decreased due to consumption (as a result of ongoing thrombin generation), impaired synthesis (as a result of a negative acute phase response), and degrada-tion by elastase from activated neutrophils.56,57 A reduction in
Proinflammatory Cytokines
Mononuclear Cells
Tissue Factor-Mediated Thrombin
Generation Expression
Impairment of Anticoagulant Mechanisms
Modulation ofInflammation
(Micro) Vascular Thrombosis
Vascular Endothelial Cells
Inhibition of Fibrinolysis Due to
Increased PAI-1
FIGURE 123.1 Schematic representation of pathogenetic pathways involved in the activation of coagulation in sepsis. During sepsis, both perturbed endothelial cells and activated mononuclear cells may produce proinfl ammatory cytokines that mediate coagulation activation. Activation of coagulation is initiated by TF expression on activated mononuclear cells and endothelial cells. In addition, downregulation of physiologic anticoagulant mechanisms and inhibition of fi brinolysis by endothelial cells will further promote intravascular fi brin deposition. PAI-1; plasminogen activator inhibitor type 1.
Marder_Chap123.indd 1455
8/24/2012 4:48:18 PM
8-1/2” X 11” — FOLDS IN THIRDS TO 8-1/2” X 3-11/16”
• NEW! Stay on top of the latest information with a new section on Hemostatic and Thrombotic Disorders Associated with Systemic Conditions, which includes material on pediatric patients, women’s health issues, cancer, sickle cell disease, and other groups.
• NEW! Refresh your understanding of basic sciences related to the fi eld through new introductory chapters.
• NEW! Quickly fi nd the information you need by searching the book and image bank on the new online companion website.
• Gain fresh, authoritative perspectives on bleeding disorders and the management of patients with these and related problems from a new team of editors, each an expert in his fi eld.
• Stay current with the most up-to-date information on normal biochemistry and function of platelets and endothelial cells.
• Expand your knowledge of the pharmacology of anticoagulant, fi brinolytic, and hemostatic drugs through in-depth discussions.
Expertly manage coagulation disorders with the pre-eminent book in the fi eld.More than 160 of the world’s most renowned hematologists, vascular surgeons, and oncologists review current scientifi c discoveries, share their most successful approaches, and present promisingnew therapies.
NEWEDITIONNow in
Full Color!
See reverse for more details …
is extensive cross-talk between infland interestingly, systemic activation of coagulation and inflmation in sepsis can have some organ-specifi
Initiation of Coagulation ActivationSystemic activation of coagulation in patients with sepsis has been considered to be a result of direct activation of the con-tact system by microorganisms or endotoxin.has become apparent that the principal initiator of thrombin generation in sepsis is tissue factor (TF), without significhange in markers refl
tem.44,45 Furthermore, abrogation of the TF/factor VII(a) path-way by monoclonal antibodies completely inhibits thrombin generation in endotoxin-challenged chimpanzees and pre-vents DIC and mortality in baboons that are infused with Escherichia coli33,46,47
TF is a transmembrane 45 kDa protein, that is constitu-tively expressed on a number of cells throughout the body.The majority of these cells are in tissues not in direct contact with blood, such as the adventitial layer of large blood vessels. However, TF gets into contact with blood upon disruption of the vascular integrity, or if cells present in the circulation are altered to express TF. In sepsis, circulating mononuclear cells, stimulated by proinfl ammatory cytokines, express TF, but other stimulated by proinfl ammatory cytokines, express TF, but other stimulated by proinflthan in severe meningococcemia,ex vivo TF expression on monocytes of septic patients or experi-mental animals. However, low dose endotoxemia in healthy subjects results in a 125-fold increase in monocyte TF mRNA levels.50 Another source of TF may be on polymorphonuclear cells,51 although it is unlikely that these cells actually synthesize
FIGURE 123.1 During sepsis, both perturbed endothelial cells and activated mononuclear cells may produce proinflthat mediate coagulation activation. Activation of coagulation is initiated by TF expression on activated mononuclear cells and endothelial cells. In addition, downregulation of physiologic anticoagulant mechanisms and inhibition of fiendothelial cells will further promote intravascular fi
; the latter present in
The Villalta score has been
recommended for quantifying the syndrome.32 Patients with
PE without symptomatic DVT also have an increased risk of
Compression stockings
should be used to reduce the risk of PTS,33 but there are some
controversies. Once severe PTS has occurred, treatment is chal-
lenging. Some relief may be gained with intermittent pneumatic
or rutosides.36
Pulmonary hypertension (mean pulmonary artery pressure
25 mm Hg) is an incapacitating long-term sequel that has
been reported in 0.8% to 3.8% of patients 2 years after PE.37,38
It is unclear what transforms the original fragile emboli into
brotic, endothelialized obstructions that are tightly attached
to the arteries. The condition must be suspected when the
dyspnea persists or recurs without evidence of new emboli.
A screening program with echocardiography several years after
an episode of PE was not useful due to a low yield of only 0.57%
with chronic pulmonary hypertension.39 Right heart catheter-
ization is required to assess the pulmonary artery pressures
accurately, and central venous saturation and cardiac output
are needed to understand prognosis and decide on medical
Pulmonary endarterectomy is the treatment of choice
but should only be performed at highly specialized centers. The
long-term consequences of VTE are reviewed in Chapter 85.
PROPHYLAXIS OF VENOUS
Prophylactic regimens against VTE have been most extensively
evaluated in major orthopedic surgery, notably hip or knee
cacy being asymptomatic DVT
documented by venography and surgical wound bleeding serving
as a sensitive safety outcome. Recently, there has been intensive
debate around these outcomes. The value of asymptomatic
DVT as a surrogate outcome for fatal PE has been questioned.41
The European Medicines Agency has since 2007 recommended
a composite of (a) symptomatic or asymptomatic proximal
DVT, (b) symptomatic nonfatal PE, and (c) VTE-related death
or any death as the primary outcome;42 so asymptomatic distal
DVT may not be an acceptable surrogate outcome. Variations
nition of major bleeding have been used during the
and attempts have been made to harmonize
nition, published as recommendations by the Scientifi c nition, published as recommendations by the Scientifi c nition, published as recommendations by the Scientifi
and Standardization Committee of the International Society 44,45 The European Medicines
nition in their recommendations.42,46
In major orthopedic surgery, prophylaxis against VTE is
today given to a high proportion of patients, although the rec-
ommended duration and start time are not followed for over
Overall compliance with guidelines in surgical
patients is 58.5%, and only 39.5% for medically ill patients,
according to the ENDORSE survey.48 Collins et al.49 showed in
a meta-analysis of more than 70 randomized trials that prophy-
laxis with low-dose unfractionated heparin (LDUH) reduces
fatal PE in the surgical setting from 0.81% to 0.26%. In the stud-
ies in medical patients, death was not signifi cantly affected.ies in medical patients, death was not signifi cantly affected.ies in medical patients, death was not signifi
50,51
The duration of high VTE risk was recently addressed by the
EXCLAIM trial by evaluating extended prophylaxis with LMWH
h prolongation of prophylaxis
to 28 days reduced the incidence of VTE, this occurred at the
cant increase in major bleeding,52 a phenomenon
CHAPTER 63 ■ INHERITED THROMBOCYTOPENIAS 787
VWD2B (V1316M)BSS
Giant Granule
MYH9MYH9
MC
AML-1
Proplatelet
GPS
AbnormalMyosin
DöhleBody
Absence ofα-Granules
Control Control Patient
FIGURE 63.1 Composite illustration showing some of the striking ultrastructural characteristics of platelets in selected inherited thrombocytopenias. In the upper panels are shown the typical large round platelets of a patient with the BSS as seen by electron microscopy. Note the heterogeneous distribution of a-granules but the absence of large MC. Adjacent are platelets from a vWD2B patient showing size heterogeneity. An enlarged a-granule is highlighted. The middle panels fi rst show electron microscope images of large round platelets from a patient with MYH9-related disease (May-Hegglin anomaly); note the large abnormal platelets with abundant MC. Also shown are a cytochemically stained Döhle-like inclusion and NMMHC-IIA immunoprecipitates detected by immunofl uorescence in leukocytes from the same patient. In the lower panel is fi rst shown platelet anisotropy in a patient with amegakaryocytic thrombocytopenia with predisposition to leukemia (AML-1). Platelets are immature and proplatelet fragments are present. Finally two platelets from a patient with the GPS are shown. These platelets are totally lacking a-granules. Bars = 1 mm
Marder_Chap63.indd 787 8/29/2012 11:05:40 AM
Now with more than 700
illustrations!
2-A434 Marder flyer.indd 1 10/17/12 8:40 PM
© Wolters Kluwer Health/Lippincott Williams & Wilkins 2-A434Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103
1058 PART IV ■ THROMBOTIC DISORDERS
T lymphocytes comprise an important component of the leu-
kocytic infi ltrate in human atheroma. T cells, when activated,
can secrete interferon g (IFN-g), an inhibitor of SMC colla-
gen synthesis.8 Considerable evidence supports the activation
of T cells in human atheroma and the presence of IFN-g.163
Therefore, impaired ability of SMCs to synthesize new colla-
gen to reinforce and maintain the extracellular matrix of the
fi brous cap can also lead to thinning and weakening of the
structure, characteristic of plaques that tend to rupture and
cause thrombosis.164
Indeed, SMCs may serve an important function as protec-
tors of the plaque’s fi brous cap, due to their ability to synthe-
size collagen and other structurally important components
of the arterial extracellular matrix (FIGURES 89.9 and 89.10). In
this regard, SMC death within atheroma may promote plaque
disruption.122 As noted earlier, infl ammatory pathways in ath-
eroma likely promote apoptosis. In particular, combinations
of infl ammatory cytokines can trigger cell death by apop-
tosis in human SMCs in vitro.165 Moreover, activated T cells
within lesions, by expression of Fas ligand, can engage Fas on
the surface of SMCs and, in conjunction with infl ammatory
cytokines including IFN-g, trigger the deaths of these cells.149
Therefore, just as in the case of superfi cial erosion, where
ECs are the target, fi brous cap rupture may depend on both
proteolysis and cell death. Infl ammatory pathways appear to
participate decisively in the destabilization of the plaque that
triggers thrombosis in both superfi cial erosion and fi brous cap
rupture.
Lipid Core
Fibrous CapFibrous Cap
• Thin Fibrous Cap
• Large Lipid Pool
• Less Stenotic Lesions
• ↑ (Ester/Free) Cholesterol
• ↓ Collagen Synthesis
• ↑ Collagen Degradation
• ↑ Macrophages, T-Cells
• ↓ Smooth Muscle Cells
Factors Increasing Stress Factors Weakening the Cap
MediaMedia
IntimaIntima
FIGURE 89.9 Biomechanical and biochemical features contribute to
disruption of atheromatous plaques and their thrombotic complica-
tions. See text for explanation. (From Lee R, Libby P. The unstable
atheroma. Arterioscler Thromb Vasc Biol 1997;17:1859–1867, with
permission.)
FIGURE 89.10 Molecular mechanisms regulating the stability of atheroma. The vascular SMCs synthesize the collagen and
elastin in the atheroma’s fi brous cap. When infl ammation is present, as characteristic of plaques that cause fatal thrombo-
ses, interferon g (IFN-g) secreted by activated T cells may inhibit collagen synthesis, impeding the repair and maintenance
of the collagenous framework of the plaque’s fi brous cap. The activated macrophage secretes proteinases that can degrade
both collagen and elastin. The breakdown of these structural molecules of the extracellular matrix can weaken the fi brous
cap, rendering it particularly susceptible to rupture and precipitation of the thrombotic complications of atheroma. The
macrophage, in turn, undergoes activation by IFN-g derived from the T lymphocytes and by CD40 ligand (CD154) expressed
on the surface of these cells. Platelets also can express active CD40 ligand. Plaques contain other activators of macrophages
not derived from T cells, including tumor necrosis factor-a (TNF-a), macrophage-colony–stimulating factor (M-CSF), and
macrophage chemoattractant protein-1 (MCP-1), among others. (After Libby P. Molecular bases of the acute coronary
syndromes. Circulation 1995;91:2844–2850, with permission.)
atheromatous lesions can elaborate gelatinases, including MMP-2,
MMP-9,157 and MMP-14, among many other proteinases.162
The interstitial forms of collagen that lend strength to
the plaque’s fi brous cap can also diminish in vulnerable
plaques because of decreased de novo synthesis by SMCs.
Marder_Chap89.indd 1058
8/24/2012 4:14:44 PM
Hemostasis and Thrombosis: Basic Principles and Clinical Practice, Sixth EditionVictor J. Marder, MD • William C. Aird, MD • Joel S. Bennett, MDSam Schulman, MD • Gilbert C. White, II, MD1,616 pages • 777 illustrations, 633 in full color • ISBN: 978-1-60831-906-0
No other book is as inclusive in scope, offering expert coverage of the fi eld from the standpoint of both basic scientists and clinicians—enabling you to fully understand the science behind hemostasis, blood coagulation, and thrombosis.
• NEW! Enhance your understanding of bleeding and thrombotic disorders through more than 600 full-color detail-revealing illustrations.
• NEW! Access broad topics of general importance in new section-overview chapters.
• UPDATED! Find clinical answers fast through hundreds of quick reference charts that offer guidance on selecting and administering therapies.
• UPDATED! Access the latest research quickly and easily through this edition’s wealth of up-to-date references.
Bring state-of-the-art science to your expert management of clotting disorders.
Save $40 off the list price when you order by December 31, 2012.
LWW.com/MarderLWW.com savings code: WCA434RD
1-800-638-3030 Phone savings code: DCA434ZZ
Mail the enclosed order form in the postage-paid envelope
Order with your smartphone now
ScanScan
Scan
NEW BONUS website features completely searchable text and an image bank!
Scan
NEW EDITION
$399.00 $359.00
2-A434 Marder flyer.indd 2 10/17/12 8:40 PM
