Page 2233 - Williams Hematology ( PDFDrive )

2208 Part XII: Hemostasis and Thrombosis Chapter 129: Disseminated Intravascular Coagulation 2209

the ability of many malignant cells to express urokinase-type plasmino- virtually identical in trauma patients and septic patients. The levels
214
gen activator and t-PA, most tumors induce a hypofibrinolytic state. of TNF-α, IL-1β, PAI-1, circulating TF, plasma elastase derived from
Because DIC is commonly characterized by a shutdown of the fibrino- neutrophils, and soluble thrombomodulin all can be elevated in patients
lytic system, mostly because of high levels of PAI-1, this may represent with signs of DIC, predicting multiorgan dysfunction (ARDS included)
an alternative mechanism for the development of DIC in cancer. and death. 215,216 Careful monitoring of laboratory signs of DIC, reduced
Virtually all pathways that contribute to the occurrence of DIC fibrinolytic activity, and perhaps low AT levels also are useful for pre-
are driven by cytokines. IL-6 has been identified as one of the most dicting the outcome of such patients. 217
important proinflammatory cytokines that is able to induce TF expres- DIC can be aggravated in patients with severe trauma who require
sion on cells. 21,199 Indeed, inhibition of IL-6 results in an inhibition of massive blood replacement because stored blood components are
endotoxin-stimulated activation of coagulation. In contrast, changes diluted and do not contain sufficient amounts of viable platelets and
in fibrinolysis and microvascular physiologic anticoagulant pathways factors V and VIII. Moreover, in such patients, there is an activation of
are mostly dependent on TNF-α. 200–202 Other cytokines that participate fibrinolysis that further aggravate bleeding in combination with acido-
in the systemic activation of coagulation are IL-1β and IL-8, whereas sis, and hypotension. 218–221 Infection commonly occurs in such patients
antiinflammatory cytokines, such as IL-10, are able to inhibit DIC. 203–205 and may contribute to the DIC.
Because many types of tumors have the ability to synthesize and release The time interval between trauma and medical intervention cor-
cytokines or to stimulate other cells to activate the cytokine network, relates with the development and magnitude of DIC. Experience during
it is likely that cytokine-dependent modulation of coagulation and wars proved that fast evacuation and prompt medical care reduce the
fibrinolysis plays a role in cancer-related DIC. risk of DIC. 222–224
Patients with solid tumors are vulnerable to risk factors and addi-
tional triggers of DIC that can aggravate thromboembolism and bleed- BRAIN INJURY
182
ing. Risk factors include advanced age, stage of the disease, and use of
197
chemotherapy or antiestrogen therapy. Triggers include septicemia, Brain injury can be associated with DIC, most likely because the injury
immobilization, and involvement of the liver by metastases that impede exposes the abundant TF of brain to blood. Specimens of contused brain,
the function of the liver in controlling DIC. Microangiopathic hemo- obtained during surgery in patients with head injury and of liver, lungs,
lytic anemia frequently is induced by DIC in patients with malignan- kidneys, and pancreas obtained during autopsy, revealed microthrombi
cies and is particularly severe in patients with widespread intravascular in arterioles and venules. 225,226 In adults and children with head injuries,
227
metastases of mucin-secreting adenocarcinomas. 206 a high rate of mortality occurred when DIC was present. A labora-
tory DIC score has predictive value for prognosis in patients with head
injuries, thereby supplementing the Glasgow coma score. Bleeding
228
LEUKEMIAS in patients with DIC that is related to brain injury can be managed by
Numerous reports on DIC and fibrinolysis complicating the course of replacement therapy.
acute leukemias have been published. In 161 consecutive patients who
presented with acute myeloid leukemia, DIC was diagnosed in 52 (32 BURNS
percent). In acute lymphoblastic leukemia, DIC was diagnosed in
207
15 to 20 percent. Some reports indicate that the incidence of DIC in TF exposed to blood at sites of burned tissue, the systemic inflam-
208
acute leukemia patients might further increase during remission induc- matory response syndrome induced by the burn, and the common
229
tion with chemotherapy. In patients with acute promyelocytic leuke- presence of superimposed infections, all can trigger DIC. Bleeding,
209
mia (APL), DIC is present in more than 90 percent of patients at the laboratory tests indicative of DIC, and vascular microthrombi in biop-
time of diagnosis or after initiation of remission induction. 210,211 sies of undamaged skin have been described in patients with extensive
230
The pathogenesis of hemostatic disturbance in APL is related to burns. Kinetic studies with labeled fibrinogen and labeled platelets
properties of the malignant cells and their interaction with the host’s disclosed that, in addition to systemic consumption of hemostatic fac-
231
endothelial cells. 192,208 APL cells express TF and the cancer procoagulant tors, significant local consumption occurs in burned areas. Labora-
that can initiate coagulation, and they release IL-1β and TNF-α, which tory signs of DIC are associated with organ failure; the extent of protein
230
downregulate endothelial thrombomodulin, thereby compromising C and AT deficiencies correlates with a poor outcome. A clinico-
the protein C anticoagulant pathway. APL cells also express increased pathologic study of 139 patients who died during treatment for a severe
amounts of annexin II, which mediates augmented conversion of plas- burn disclosed that 18 percent had cerebral infarctions caused by septic
minogen to plasmin (Chap. 135). The overall results of these processes arterial occlusions or DIC and approximately 4 percent had intracranial
are DIC and hyperfibrinolysis, followed by major bleeding that can hemorrhage. 232
lead to death. All-trans-retinoic acid, used for induction and main-
212
tenance therapy of APL, inhibits in vitro and in vivo the deleterious LIVER DISEASES
effect of APL cells and has led to a reduced frequency of early hemor- Very complicated derangements of hemostasis occur in patients with
rhagic death; however, all-trans-retinoic acid may induce thrombotic severe liver disease and during liver transplantation (Chap. 129). Syn-
complications. 192,213 thesis of most coagulation factors and natural anticoagulants (protein
C, protein S, and AT) and of the main components of the fibrinolytic
system (plasminogen, TAFI, and α -antiplasmin) is reduced. The capac-
TRAUMA ity of the liver to clear the circulation of activated factors IX, X, and XI,
2
When DIC complicates trauma, it usually occurs in severely injured and of t-PA is decreased. Moreover, thrombocytopenia is common as a
patients. Extensive exposure of TF to the blood circulation and hemor- result of hypersplenism and decreased production of thrombopoietin
rhagic shock probably are the most immediate triggers of DIC in such by the liver. The similarities between the hemostatic defects observed
instances, although direct proof of this mechanism is lacking. An alter- in patients with liver disease and in patients with DIC are striking and
native hypothesis is that cytokines play a pivotal role in the occurrence have evoked an ongoing controversy as to whether or not DIC contrib-
of DIC in trauma patients. In fact, the changes in cytokine levels are utes to hemostatic derangements associated with liver disease. 233

Kaushansky_chapter 129_p2199-2220.indd 2208 17/09/15 3:46 pm