Page 1239 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

846 PART 7: Hematologic and Oncologic Disorders

the subgroup of ICU patients. In large prospective study of 10,866 adult integrity, pathologic consumption of platelets, and activation of both
medical patients without bleeding prior to admission, the rate of bleed- platelet and coagulation cascades, which may be clinically visible as
ing after general hospital admission was observed to be 3.2%. 8 palpable purpura or antineutrophil antibody-associated pulmonary
Additional inferences about the risk of bleeding and bleeding compli- hemorrhage. Finally, sepsis and the systemic inflammatory response
cations in critically ill patients may be drawn from examination of events syndrome may result in disseminated intravascular coagulation and pro-
in disease-specific cohorts and placebo cohorts of therapeutic interven- found disruption of microvascular function causing end-organ ischemia
tion trials. Because these observations were conducted in trial-eligible and dysfunction.
tions. The rate of clinically important gastrointestinal bleeding among a ■ PLATELET PHYSIOLOGY AND FUNCTION
patients, caution is necessary when extrapolating to general ICU popula-
prospective cohort of adult ICU patients has been observed at 1.5% with The normal function of platelets in thrombus formation includes three
risk factors including respiratory failure and coagulopathy. For patients overlapping events: platelet adhesion to sites of vascular injury, platelet-
9
requiring mechanical ventilation, the rate of upper gastrointestinal platelet adhesion and aggregation, and platelet activation. Platelet
bleeding is higher than the general ICU population (2.8%). In medical- adhesion to exposed subendothelial collagen fibrils is mediated by
surgical patients eligible for heparin thromboprophylaxis, meta-analysis interaction of platelet membrane glycoprotein receptors with subendo-
of placebo patients (n = 1072 patients) and patients receiving any type thelial collagen matrix and circulating von Willebrand factor. Disorders
of heparin (n = 1084) demonstrate rates of any major bleeding of 4.9% of platelet glycoprotein receptors cause failure of platelet adhesion as
and 4.0%, respectively. Similarly, in patients receiving either dalteparin well as failure of platelet-platelet binding and aggregation. Although
10
or heparin thromboprophylaxis, the overall rate of bleeding was 5.6% rare, these adhesion diseases do result in clinical bleeding disorders
with identified risk factors of lower platelet count, therapeutic heparin, such as the Bernard-Soulier syndrome (glycoprotein Ib platelet receptor
antiplatelet agents, renal replacement therapy, and recent surgery. deficiency). Related disorders of impaired platelet binding include von
5
Finally, placebo cohorts of critically ill patients in severe sepsis trials Willebrand disease which results from either quantitative or qualitative
demonstrate rates of clinically important or life-threatening bleeding as deficiency of von Willebrand factor, which is an essential cofactor in
low as 1% to 2% and as high as 12% to 15%. 11-14 platelet-endothelial and platelet-platelet attachment. 23
Platelet activation causes release of platelet granule contents and
PHYSIOLOGY AND MECHANISM morphologic changes. Platelet activation results from platelet glycopro-
OF NORMAL COAGULATION tein receptor attachment to collagen as well as thrombin binding to the
PAR1 platelet thrombin receptor. Platelets are also strongly activated
Blood clot formation and maintenance of vascular patency depends on by binding circulating fibrin to integrin glycoprotein receptor IIb/IIIa,
the highly complex interaction of vascular endothelium, vascular sub- also known as integrin α(IIb)β(3) receptor. These parallel pathways
endothelial matrix, platelets, and soluble coagulation proteins. Normal of activation promote rapid and synergistic activation of platelet plug
thrombus formation and subsequent dissolution result from closely formation and coagulation cascade activation at sites of vascular injury.
regulated enzymatic activity of the coagulation factors, vascular endo- Platelet activation is characterized by increased platelet thromboxane
thelial cell surface protein expression, and recruitment and activation A2 synthesis, protein phosphorylation, release of intracellular calcium,
of platelets at the site of injury. Common clinical conditions including and subsequent changes in platelet shape and granule secretion.
24
infection, shock, surgery, and trauma profoundly affect vascular endo- Rapid platelet degranulation releases strongly activating, procoagulant
thelial function and coagulation pathways. The physiology of blood substances including adenosine diphosphate (ADP), thromboxane A2,
15
clot propagation and resolution in these clinical conditions give rise to calcium, serotonin, and platelet factor 4. These events in turn promote
multiple distinct clinical disorders. However, the final common result of activation of surrounding platelets and platelet-platelet aggregation
abnormal clotting is impaired oxygen delivery to organs and tissues as mediated by fibrin cross-linking of platelets with the IIb/IIIa receptor.
25
the result of extravascular blood loss, altered vasoregulation, and intra- The primary mechanisms of pharmacologic inhibition of platelet-
vascular occlusion by thrombosis. mediated coagulation involve inhibition of platelet prostaglandin
■ VASCULAR PHYSIOLOGY AND THROMBOSIS FACTORS synthesis (aspirin), platelet ADP binding at the P2Y12 receptor (clopi-
dogrel, ticlopidine, prasugrel), and inhibition of the IIB/IIIa receptor
Vascular endothelial cells and the subendothelial matrix maintain (abciximab, tirofiban, eptifibatide).
regulating platelet adhesion, platelet activation, and the activation of ■ SOLUBLE CLOTTING FACTORS AND COAGULATION CASCADE
an equilibrium of coagulation activation and inhibition by directly
soluble clotting factors. Normal vascular endothelium produces nitric The coagulation cascade results from a stepwise activation of proen-
oxide and prostacyclins that inhibit platelet adhesion and aggregation. zymes to active enzymes followed by rapid amplification of coagulation
During massive injury and bacterial infection, lipopolysaccharide and activity and generation of fibrin. The coagulation cascade can be sepa-
inflammatory cytokines mediate increases in vascular endothelial cell rated into discrete events that occur during normal clot formation and
production of procoagulant microparticles, tissue factor, and plasmino- resolution. These steps are activation of thrombin from prothrombin,
gen activator inhibitor-1, with a concomitant decrease in expression conversion of fibrinogen to fibrin, propagation and amplification of
of thrombomodulin, protein C receptor, and tissue-type plasminogen thrombin production, termination of thrombin activation, elimination
activator. 16-19 Vascular endothelial cell damage and mechanical trauma of active thrombin, and enzymatic fibrin lysis (Table 90-3; Fig. 90-1).
also expose subendothelial collagen and tissue factor, which activate Beyond the immediate role of coagulation proteins in generation and
both platelets and thrombin. Platelets adhere to sites of vascular injury resolution of thrombus, these enzymes have central roles in the activa-
through direct interaction of platelet receptors glycoprotein VI, Ia/IIa, tion and modulation of infection and inflammation. 15,26
and Ib-V-IX complex with the collagen and von Willebrand factor of By convention, the activation of the coagulation cascade has been
the exposed vessel wall. 20-22 Once adherent, platelets become rapidly organized into pathways that reflect the early understanding of coagula-
activated and release procoagulant granules, leading to recruitment and tion events and tests of coagulation function. These conceptual path-
activation of more platelets. ways are reflective of laboratory techniques to activate the coagulation
The central role of vascular function and integrity in critical illness cascade. The role of these pathways during in vivo illness may not be
is visible at the bedside in routine clinical practice. Dysfunction of reflected by laboratory pathway times. In particular, the tissue factor
the vascular endothelium resulting from atherosclerosis leads directly and contact activation pathways do not account for the role of multiple-
to pathologic thrombosis and acute coronary syndrome. Perivascular factor complexes and platelet surface interactions in clot formation. The
inflammation and injury in vasculitis disorders results in loss of vascular advantage of these coagulation pathway concepts is that they facilitate

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