• Quantitative deficiencies of hematopoietic cells and hemostatic proteins are common in the critical care setting.
• Deficiencies are frequently multiple and acquired rather than congenital.
• Deficiency states can be due to a combination of decreased production, loss from the intravascular space, increased consumption, and premature destruction.
• Localized bleeding usually responds to treatment, but generalized bleeding from two or more sites simultaneously often reflects a breakdown of hemostatic homeostasis and indicates disseminated intravascular coagulation.
• Hemostasis is usually adequate if the hematocrit is above 30 per cent, the platelet count is above 80 * 10 9/l, the fibrinogen is above 1 g/l, and the activated partial thromboplastin time and partial thromboplastin time are no more than 3 to 5 s longer than control values.
Blood consists of cellular and fluid plasma components. Red cells, white cells, and platelets originate in the bone marrow, while plasma proteins are synthesized primarily in the liver. In common with most physiological systems, cell numbers and plasma protein concentrations are regulated within narrow limits under normal conditions (Table J). Frequently recognized hematological abnormalities in the critically ill are predominantly quantitative; qualitative defects are rare. Likewise, most hematological abnormalities are secondary to non-hematological single- or multiple-organ pathology. Acquired defects are much more common than congenital defects, and multiple abnormalities of both cellular and hemostatic components are more frequent than the single defects usually identified in routine hematological practice.
Anatomically, the cellular components comprise cells in circulating blood, bone marrow, lymph nodes, and spleen. Red cells are primarily concerned with oxygen carriage, white cells with immunity and control of infection, and platelets with maintaining vascular integrity. The hemostatic system is responsible for maintaining blood fluidity and, at the same time, prevents blood loss by initiating rapid, localized, and appropriate blood clotting at sites of vascular damage. This system is complex, comprising both cellular and plasma elements, i.e. platelets, coagulation and fibrinolytic cascades, the natural anticoagulation pathway, and endothelial cells.
Hematopoiesis, the production of the cellular elements, occurs in adults within the marrow spaces of the bones of the axial skeleton. Hematopoiesis originates from the pluripotent stem cell which has the capacity for both replication, to maintain stem cell numbers, and differentiation, by which it gives rise to cells of the erythroid, myeloid, and lymphoid series as well as megakaryoctes, which are the precursors of platelets ( Fig 1). Development and differentiation of hemopoietic cells is under the control of glycoprotein cytokines which operate in a paracrine or endocrine fashion. These act at early, intermediate, and late stages of cell differentiation; target cell responsiveness depends upon both cytokine production and expression of specific receptors on the target cells. Early-acting cytokines include stem cell factor and interleukin 3, while cytokines acting on more differentiated cells include granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, thrombopoietin, the recently described platelet growth factor, and erythropoietin, produced in the kidney and controlling erythropoiesis. Availability of human recombinant forms of these proteins has resulted in their usage in the treatment of anemic and neutropenic states under some circumstances. There are also inhibitory cytokines (e.g. tumor necrosis factor, transforming growth factor, and, probably, interleukin 2) which act in a negative regulatory manner to inhibit hematopoiesis. These are implicated in pathological conditions resulting in the suppression of hematopoiesis, in particular the anemia of chronic disorder.
Erythrocytes are the most common circulating hemopoetic cells. The precursor forms within the marrow are nucleated but, when released into the peripheral blood, they no longer contain a nucleus. Red cells have a finite lifespan of around 120 days, at which time they are destroyed primarily in the reticuloendothelial system. Red cells recently released from the bone marrow contain trace amounts of RNA that can be stained with supravital stains and recognized as reticulocytes. The reticulocyte count can give a vital insight into the synthetic function of the marrow. Red cell numbers can be decreased by loss from the body (hemorrhage), failure of synthesis due to primary marrow disease or deficiency of iron, vitamin B12, and folate, depressed erythropoiesis in the anemia of chronic disease, and premature red cell destruction (hemolysis). Measurement of hemoglobin concentration depends not only on the number of red cells present and their individual hemoglobin content, but also on the plasma volume in which they are distributed. A diminished plasma volume will spuriously elevate hemoglobin, while depletion of red cells and hemoglobin will be masked if there is concomitant loss of plasma volume. Consequently, measurement of plasma volume and red cell mass using isotopic techniques can sometimes be highly informative.
White cells divide into five groups, namely neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Neutrophils, which form the majority, function primarily as a defense mechanism against pathogenic bacteria and have a relatively short half-life of about 6 h. A significant proportion are in a marginating rather than a circulating pool which can be rapidly mobilized, leading to the rapid development of a neutrophil leukocytosis following physiological stress, infection, trauma, burns, etc. Lymphocytes can be divided into B, T, and natural killer cells. B cells are particularly important in the humoral immune response, while T cells are primarily involved in the cellular immune response. It is becoming increasingly clear that B and T cells must act together for efficient functioning of the body's immune system.
Platelets are highly organized and structured particles of megakaryocyte cytoplasm. They contain no nuclei but express specific surface glycoproteins allowing them to bind to adhesive endothelial, subendothelial, and plasma proteins. They can undergo adhesion, aggregation, and subsequently a release reaction which liberates the contents of granules contained within their cytoplasm, resulting in augmentation of the aggregation reaction. Activated platelets also provide a negatively charged phospholipid surface upon which proteins of the coagulation cascade can assemble. Although they are individually very small, aggregated platelets form a platelet plug which can block vascular defects and precipitate a stabilizing fibrin mesh over the top. To perform this task efficiently, platelets need to be present in sufficient numbers and have normal function. Normal hemostasis, assuming normal platelet function, is maintained with platelet counts above 80 * 10 9/l; diminution below this level results in a progressively prolonged bleeding time. At levels below 20 * 10 9/l there is a much heightened risk of spontaneous hemorrhage.
The requirement for blood to remain fluid while confined to the intravascular compartment, but to clot rapidly when the vessel is damaged or breached, and the need for this response to be rapid, localized, and self-limiting has resulted in the evolution of a complex hemostatic mechanism encompassing the coagulation and fibrinolytic cascades, platelets, the natural anticoagulant pathway, and endothelial cells themselves ( Table., 2). The coagulation cascade consists of a stepwise series of reactions in which circulating inactive zymogen serine proteases are sequentially activated by proteolytic cleavage, resulting in the formation of active enzymes (Fig.,2). These multiple steps allow both biological amplification and multiple points of control. Although the coagulation cascade was historically divided into intrinsic and extrinsic pathways, it is clear that, under the vast majority of physiological circumstances, coagulation is activated by tissue factor exposure and hence proceeds down the extrinsic pathway. However, the tissue factor-factor Vila complex can activate both factor X and factor IX, which has resulted in an extension of the final common pathway. The physiological role of the intrinsic pathway is unclear; in addition to initiating coagulation, activation of factor XI and factor XII also results in activation of the fibrinolytic cascade and the complement system, and the generation of vasoactive inflammatory proteins such as bradykinin. The purpose of the coagulation cascade is to generate the enzyme thrombin which cleaves soluble fibrinogen to form insoluble fibrin. Thrombin is also able to initiate a potent positive feedback pathway whereby thrombin activates factors V and VIII into their activated form; these increase the catalytic efficiency of the generation of factors Xa and IIa generation by over 1000-fold. Thrombin is also a potent initiator of platelet aggregation. Uncontrolled generation of thrombin is the hallmark of disseminated intravascular coagulation; thus thrombin generation is tightly regulated by the natural anticoagulant pathway ( Fig 3). This consists of antithrombin, a potent and rapid inhibitor of free thrombin which acts as a suicide substrate, rapidly neutralizing thrombin by forming thrombin-antithrombin complexes in which thrombin is devoid of proteolytic activity. In addition, free thrombin is bound by the protein thrombomodulin, which is expressed on the endothelial cell surface and alters the substrate specificity of thrombin. As a result, it is no longer able to clear fibrinogen or activate factors V or VIII but is now able to activate protein C. Activated protein C, with its cofactor protein S, degrades activated factors Va and VIIIa. Consequently, thrombin bound to thrombomodulin acts as an anticoagulant protein and initiates a feedback pathway to limit the extent of coagulation. Defects in the natural anticoagulant pathway, in the form of deficiencies of antithrombin, protein C, and protein S, are associated with a predisposition to excessive venous thrombosis known as thrombophilia. Acquired deficiencies of these proteins are extremely common in the critical care setting.
The fibrinolytic cascade is analogous to the coagulation cascade but generates the enzyme plasmin rather than thrombin. Plasmin degrades rather than generates fibrin. The fibrinolytic system is also controlled by specific inhibitors as well as feedforward and feedback pathways. Although congenital abnormalities of the fibrinolytic pathway proteins are uncommon, fibrinolytic therapy for the dissolution of thrombi in coronary and cerebral arteries and within the deep veins of the legs and pulmonary vasculature has proved effective.
Historically, endothelial cells were considered biologically neutral, lining blood vessels without apparent effect on hemostasis. It is now clear that endothelial cells are, under normal circumstances, actively anticoagulant. They produce nitric oxide and prostacyclin, resulting in vasodilatation and inhibition of platelet aggregation, express thrombomodulin to initiate the natural anticoagulant pathway on its surface, express glycosaminoglycans and heparinoids to inhibit the coagulation cascade, and produce tissue plasminogen activator to initiate fibrinolysis. However, endothelial cells which have become activated, for example by a bacterial endotoxin, no longer produce nitric oxide and prostacyclin, express tissue factor on their surface to initiate the coagulation cascade, downregulate thrombomodulin expression, and produce inhibitors of the fibrinolytic cascade rather than activators. Adhesion molecules such as von Willebrand factor and selectins are also released or expressed, resulting in an actively procoagulant endothelial cell surface.
The anticoagulant heparin acts by potentiating the thrombin-inhibiting activity of antithrombin. Unfractionated heparin prolongs the thrombin time and the activated partial thromboplastin time (APTT), by which it is monitored, but recently introduced low-molecular-weight heparins do not significantly affect APTT as they have more activity against factor Xa than thrombin. Consequently, monitoring, if necessary, requires an anti-factor Xa assay. The orally acting anticoagulant warfarin inhibits post-translational carboxylation of glutamic acid residues on coagulation factors II, VII, IX, and X, and also on proteins C and S, resulting in the synthesis of inactive forms of these proteins. Warfarin has a long half-life and complex pharmacokinetics with multiple drug interactions. A reversal of the warfarin effect may require use of fresh frozen plasma, parenteral vitamin K, or, in life-threatening situations, specific coagulation factor concentrates.
Thromboprophylaxis in patients immobilized for prolonged periods can be achieved with low doses of both unfractionated and low-molecular-weight heparins. Neither require monitoring at these doses. Thrombosis is more common in the presence of low levels of antithrombin, protein C, and protein S which can be either congenital or acquired. Acquired deficiency is extremely common in the critical care situation, where these proteins are rapidly depleted as a response to increased coagulation activation and synthesis is frequently impaired due to compromised hepatic function.
Although it may not be possible to normalize hemostatic abnormalities completely in the critically ill, bleeding will be reduced if hematocrit can be maintained above 30 per cent, platelet count above 80 * 109/l, fibrinogen above 1 g/l, and APTT and prothrombin time no more than 4 to 5 s above the upper limit of normal. Under these circumstances it is usually safe to perform invasive procedures including placement of central venous and arterial lines. Excessive bleeding under these conditions is usually due to either failure of local hemostasis (e.g. postoperatively) or the development of disseminated hemostatic failure.
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