Acquired Coagulation Disorders

George M. Rodgers

Abnormalities in blood coagulation may complicate a large number of disorders (Table 54.1). In contrast to inherited disorders in which deficiency or abnormality of a single factor is characteristic, the acquired forms usually are associated with multiple coagulation abnormalities, and the disorder often is complicated by thrombocytopenia, deficient platelet function, and abnormal inhibitors of coagulation. Because of the compound nature of the hemostatic defect, the severity of bleeding often correlates poorly with the results of laboratory tests in patients with acquired coagulation disorders, and replacement therapy may be ineffective. With some notable exceptions, however, bleeding usually is less severe than in the inherited forms, and the clinical picture often is complicated by signs and symptoms of the underlying disease.

DEFICIENCIES OF VITAMIN K-DEPENDENT FACTORS

Prothrombin; factors VII, IX, and X; and proteins C and S are synthesized by the liver by a process that depends on vitamin K (see Chapter 18 and Fig. 54.1).¹, ² When stores of this vitamin are deficient or abnormal, hypofunctional analogs of these factors are synthesized, which inhibit normal coagulation. These descarboxy analogs of the vitamin K-dependent factors do not bind to cellular phospholipid surfaces and, therefore, do not participate in cellassociated coagulation reactions. This may occur in disorders in which intake or absorption of vitamin K is deficient and in disorders that impair the biosynthetic capacity of the liver (Fig. 54.1). A similar coagulation abnormality may be produced by anticoagulant drugs such as coumarin and indanediones, which antagonize the action of vitamin K (see Chapter 55).

Vitamin K Deficiency Bleeding (Hemorrhagic Disease of the Newborn)

Hemorrhagic disease of the newborn is the result of vitamin K deficiency in the neonate; this phrase was first used more than 100 years ago.³ The preferred term is vitamin K deficiency bleeding (VKDB) in infancy as proposed by a consensus committee.⁴ Formerly a major cause of bleeding, this disorder is now uncommon because of the routine administration of vitamin K at birth⁵; however, it is still encountered in economically deprived populations.

Pathophysiology

The normal newborn has a moderate deficiency of the vitamin K-dependent coagulation factors. The plasma levels of these factors normally fall even further during the first 2 to 5 days of life, rise again when the infant is 7 to 14 days old, and attain normal adult levels later in life (see also Table 45.6). The deficiency of the vitamin K-dependent coagulation factors that is present at birth, as well as the slow rate at which adult levels are attained, presumably is the result of intrinsic “liver immaturity;” neither of these physiologic phenomena is affected by vitamin K administration.⁶ On the other hand, the diminution in levels of these factors that occurs at age 2 to 5 days is prevented by vitamin K administration because it is the result of a transitory physiologic deficiency of this vitamin. Factors that further diminish the amount of vitamin K available at this juncture and those that further impair the synthetic capacity of the liver predispose neonates to hemorrhagic disease of the newborn. These factors are (a) prematurity, (b) inadequate dietary intake, (c) delayed gut colonization by bacteria, (d) various obstetric and perinatal complications, and, possibly, (e) maternal deficiency of vitamin K.

Prematurity often has been associated with VKDB.⁷ Levels of the vitamin K-dependent factors at birth are approximately proportional to gestational age and birth weight.⁸ In premature infants, the physiologic immaturity of the liver is marked, and the response to vitamin K that is present is subnormal.

Most factors associated with deficient intake of vitamin K also delay the colonization of the gut by bacteria. These factors include delayed feeding, breast-feeding, vomiting, severe diarrhea, and antibiotics, including those present in maternal milk. Human milk and colostrum are poor sources of vitamin K,⁶ and reliance on breast milk as the sole source of nutrients in the neonatal period is an important factor in many cases of VKDB.⁵

Coumarin and indanedione drugs cross the placenta and may produce hemorrhagic disease in the newborn.⁹ Infants born of mothers who were taking diphenylhydantoin or other anticonvulsants, including barbiturates, or salicylates have developed a syndrome similar to VKDB.¹⁰ Treatment of the mother with vitamin K during the last trimester may prevent this complication.

Clinical Features and Laboratory Diagnosis

VKDB etiology is considered idiopathic (no cause other than breast-feeding) or secondary (malabsorption of vitamin K, liver
disease, drugs).⁴ VKDB can also be classified in terms of age of onset: Early (onset <24 hours of age), classic (onset usually between 3 and 5 days), and late (onset on or after 8 days). Early VKDB is uncommon and usually results from placental transfer of maternal drugs that antagonize vitamin K in the newborn. Late VKDB occurs almost exclusively in breast-fed infants who may also have hepatobiliary disease.⁴

TABLE 54.1 ACQUIRED COAGULATION DISORDERS

Deficiencies of vitamin K-dependent coagulation factors
	Hemorrhagic disease of the newborn (vitamin K deficiency bleeding) Biliary obstruction (gallstone, strictures, fistulas) Malabsorption of vitamin K (sprue, idiopathic steatorrhea, celiac disease, ulcerative colitis, regional enteritis, gastrocolic fistulas, Ascaris infestation) Nutritional deficiency Drugs
		1. Pharmacologic antagonists of vitamin K (coumarins, indandiones, others) 2. Those that alter gut flora (broad-spectrum antibiotics, sulfonamides) 3. Miscellaneous (cholestyramine)
Liver disease (see Table 54.3)
Accelerated destruction of coagulation factors
	Disseminated intravascular coagulation (see Table 54.4)
	Fibrinolysis (liver disease, thrombolytic agents, tumors, after surgery)
Inhibitors of coagulation
	Specific inhibitors (antibodies) (see Table 54.6) Antiphospholipid-protein antibodies (see Table 54.7) Miscellaneous (antithrombins, paraproteinemias)
	Miscellaneous
	After massive transfusion After extracorporeal circulation Drugs (antibiotics, antineoplastic agents, others) Other disorders (polycythemia vera, congenital heart disease, amyloidosis, nephrotic syndrome, Sheehan syndrome, Gaucher disease, leukemia, others)

FIGURE 54.1. Etiologies of vitamin K deficiency. Sources of vitamin K include the diet and gut bacterial synthesis. Processes leading to vitamin K deficiency are indicated with a solid line ending in a squiggle.

Bleeding in classic VKDB is severe.³ The most common manifestations are melena, large cephalohematomas, and bleeding from the umbilical stump and after circumcision. Generalized ecchymoses, often without petechiae, intracranial bleeding, and large intramuscular hemorrhages also may develop.³, ⁶

Laboratory diagnosis is relatively simple (Table 54.2), but physiologic differences in the results of various coagulation tests in normal neonates must be kept in mind (see Table 45.6). In infants with VKDB, the prothrombin time (PT) always is prolonged. The partial thromboplastin time (PTT) is also prolonged. Specific factor assays reveal deficiencies of prothrombin; factors VII, IX, and X; and proteins C and S. The presence of normal antigenic levels of the vitamin K-dependent factors may be demonstrated by immunoassays.¹¹ Factors V and VIII, as well as fibrinogen, are present in normal amounts. The consensus committee recommends diagnosing VKDB with a prolonged PT value, a normal fibrinogen level, and a normal platelet count.⁴

The clinician should not assume that bleeding in the neonate is invariably the result of vitamin K deficiency.⁴ In the differential diagnosis of VKDB, virtually all causes of bleeding, particularly thrombocytopenia (see Chapter 46) and disseminated intravascular coagulation (DIC) must be considered.¹² The inherited coagulation disorders (see Chapter 53) also may produce serious hemorrhage in the neonatal period, but significant prolongation of the PT is not found in the most common forms, for example, hemophilia A and hemophilia B. Umbilical bleeding and hemorrhage after circumcision are relatively less common in the inherited coagulation disorders than in VKDB.

Treatment

Vitamin K₁ (0.5 to 1.0 mg given intramuscularly) is dramatically effective in the treatment of VKDB¹³; the 0.5-mg dose appears to be more than adequate.¹⁴ Shortening of the PT may be expected within 6 hours, and normal neonatal levels of the vitamin K-dependent factors usually are attained within 24 hours of administration. An American Academy of Pediatrics consensus report has summarized recommendations of vitamin K therapy for prevention of early and late VKDB.¹⁵ Larger (2 mg) or repeated (every 4 to 8 hours) doses of vitamin K₁ may be required to counteract the effects of coumarin drugs in infants.⁶ The response in premature infants to vitamin K₁ usually is incomplete. The administration of large doses of vitamin K may produce hemolysis, hyperbilirubinemia, and even kernicterus in the neonate. These complications appear to be associated more commonly with the synthetic derivatives than with vitamin K₁, but even the latter may be dangerous in large doses.⁶

In severe cases of VKDB, the transfusion of plasma may be helpful.⁶ Concentrates of vitamin K-dependent coagulation factors are effective but have led to thrombosis and intravascular coagulation in some infants, particularly in premature infants. This result has been attributed to immaturity of the hepatic clearance functions and physiologic deficiency of antithrombin.

Because VKDB is primarily a disease of breast-fed infants,¹⁶ VKDB can be prevented by the administration of vitamin K to the mother before delivery. Most authorities, however, recommend administering vitamin K₁ to the infant. This procedure is now routine in most nurseries. Many pediatricians also recommend the
prophylactic administration of vitamin K₁ to infants 1 to 5 months of age, especially those who are breast-fed or who have a disorder that may impair vitamin K absorption.¹⁷ The usual dosage in such older infants is 50 to 100 µg daily or 1 mg monthly.

TABLE 54.2 LABORATORY FINDINGS IN ACQUIRED COAGULATION DISORDERS

	Hemorrhagic Disease of the Newborn	Severe Liver Disease	Disseminated Intravascular Coagulation	Primary Fibrinolysis	Antibodies to Factor VIII	Inhibitors of Lupus Type
Screening Tests
Platelet count^a	N	vD	D	uN	N	V^a
Prothrombin time^b	I	I	I	vI	N	V^a
Partial thromboplastin time^b	I	I	V	vI	I	I
Thrombin time^b	vI	uI	I	I	N	N
Erythrocyte morphology^a	Macrocytes	Target cells and macrocytes	Schistocytes and microspherocytes	uN	uN^a	uN^a
Specific Assays
Fibrinogen	N	vD	D	vD	N	N
Prothrombin^b	D	D	V	uN	N	vD^c
Factor V	N	uD	uD	vD	N	N^c
Factor VII^b	D	D	V	uN	N	N^c
Factor VIIIc	N	uI	uD^c	vD	D	N^c
von Willebrand factor	N	uI	vI	V	N	N
Factor IX^b	D	D	V^c	uN	N	N^c
Factor X^b	D	D	vD	uN	N	N^c
Factor XI^b	vD	vD	uN	uN^c	N	N^c
Factor XIII^d	uN	vD	uD	vD	N	N
Tests for Fibrinolysis and FDP
FDP	uN	uI	I	I	N	N^e
Plasminogen^b	vD	vD	D	D	N	N
α²-Antiplasmin	uN	vD	V	vD	N	N
Plasmin	N	vI	uI	uI	N	N
D-Dimer	uN	uN	I	uN	N	N^e
Miscellaneous Tests
Antithrombin	N	vD	vD	uN	N	N
Protein C	D	D	V	uN	N	uN
Protein S	D	D	V	uN	N	V
D, decreased; FDP, fibrin(ogen) degradation products; I, increased; N, normal; u, usually; v, variably; V, variable.
^aMay reveal effects of acute bleeding or abnormality characteristic of underlying disease. ^bResults may differ from adult norms in normal neonates. ^cOne-stage assays may yield aberrant results. ^dHypofibrinogenemia may alter results. ^eThe presence of immunoglobulin M rheumatoid factors in certain patients may lead to a false-positive result in latex-agglutination assays.

Most pediatricians would attribute the decrease in incidence of VKDB in recent years to the prophylactic administration of vitamin K. There is widespread consensus on continuing vitamin K prophylaxis to newborns.³, ¹⁵ A prospective population study in the United Kingdom found that with prophylaxis, VKDB in newborns is rare,¹⁸ whereas in developing countries, prophylaxis is not frequently used, and VKDB is common.

Other Causes of Vitamin K Deficiency

Obstruction of the biliary tract, either intrahepatic or extrahepatic, produces vitamin K deficiency because of the absence of bile salts in the gut. Complete obstruction may lead to severe coagulation abnormalities and bleeding within 2 to 4 weeks. This was a major obstacle to surgical procedures on the biliary tract before the discovery of vitamin K.

Most malabsorption syndromes and various other chronic gastrointestinal disorders also may give rise to vitamin K deficiency. Such disorders include celiac disease, sprue, gastrocolic fistulas, ulcerative colitis, regional enteritis, extensive gut resections, protracted diarrhea of any cause, Ascaris infestations, and cystic fibrosis. The last named disorder often is complicated by liver disease.¹¹ Severe abnormalities of coagulation and bleeding are less common in association with these disorders than with biliary obstruction, presumably because absorption of vitamin K is seldom completely deficient.

Because vitamin K normally is available from two independent sources (Fig. 54.1), neither nutritional deficiency nor gut sterilization alone produces deficiency of a degree that results in significant coagulation abnormalities. In normal adults, the daily oral intake of vitamin K must be reduced to 20 µg or less for several weeks to produce significant hypoprothrombinemia.¹ However, vitamin K deficiency is more common than is usually realized in hospitalized patients with poor or negligible oral food intake, especially if they are also taking antibiotics.¹⁹, ²⁰ Significant coagulation abnormalities may arise with surprising rapidity
in such patients, and when unsuspected, they may be confused with DIC or may first be revealed by serious, unexpected postoperative hemorrhage. Antimicrobial agents presumably impair vitamin K production by inhibiting the synthesis of menadiones by gut bacteria, but they may also directly affect carboxylation reactions.²¹, ²² Vitamin K deficiency also may result from use of drugs other than antimicrobial agents, such as cholestyramine,²³ which acts by binding bile salts, or mineral oil and other cathartics when used for protracted periods. Vitamin E may antagonize the metabolic action of vitamin K and potentiate the action of coumarins.⁶ When taken in large doses, this vitamin may prolong the PT.²⁴ Antibiotic therapy, poor diet, or any of the aforementioned disorders may predispose patients to coumarin toxicity (see Chapter 55).²⁵ Large doses of aspirin, as given to treat rheumatic disorders or in amounts associated with overdosage of the drug, may also induce vitamin K deficiency.²⁶

Treatment

In adults, the parenteral administration of 10 mg of vitamin K₁ abolishes coagulation abnormalities within 12 to 24 hours if they are the consequence of a deficiency of this vitamin. Failure of vitamin K to normalize the PT is evidence for the presence of a complicating process, such as liver disease or DIC, or super-warfarin ingestion.²⁷ The synthetic vitamin K₃ (menadiones) may be absorbed in the absence of bile salts and in various malabsorption syndromes. However, these congeners of vitamin K have a more transient effect than the natural forms of this vitamin and offer minimal therapeutic advantage in the usual case. Replacement therapy with fresh frozen plasma or prothrombin complex concentrates (PCCs) is effective in the treatment of emergent vitamin K deficiency.

Intravenous administration of vitamin K may produce hemolytic anemia in patients with inherited deficiencies of various red cell enzymes, and may be associated with a risk of anaphylaxis.²⁸ Malnourished patients receiving broad-spectrum antibiotic therapy should receive vitamin K prophylactically, 5 mg twice weekly, orally or subcutaneously.²⁹

Commercially available rodenticides (super-warfarins) that exhibit long-acting vitamin K antagonism have been associated with significant bleeding disorders when these compounds have been ingested by humans.²⁷ These drugs are chemically distinct from warfarin, are 100 times more potent than warfarin, and can induce vitamin K deficiency lasting for months. In 1995 alone, more than 13,000 people were exposed to these agents and treated.³⁰ Initial treatment of these patients may require up to 100 mg of vitamin K daily to normalize vitamin K metabolism.³⁰

LIVER DISEASE

Virtually every hemostatic function may be impaired in patients with severe hepatic disease (Table 54.3)³¹, ³², ³³ as the result of failure of both the biosynthetic and clearance functions of the liver. The pathophysiology of some of these abnormalities is tied to thrombocytopenia (see Chapter 46), platelet dysfunction (see Chapter 52), intravascular coagulation and fibrinolysis, and the effects of products of fibrinogen catabolism on hemostasis (see below).

Pathophysiology

Thrombocytopenia

Patients with significant liver disease have portal hypertension, splenomegaly, and splenic sequestration of platelets, contributing to thrombocytopenia. The liver is also the major site of production of thrombopoietin, the principal humoral factor involved in megakaryocyte maturation and platelet formation (see Chapter 15). Recent studies have evaluated whether deficient levels of thrombopoietin occur in liver disease. Results indicate that thrombocytopenia in liver disease is not explained by deficient hepatic production of thrombopoietin.³⁴, ³⁵ However, there is a correlation between the extent of liver disease and platelet expression of the thrombopoietin receptor, c-Mpl,³⁵ and this reduced expression may contribute to thrombocytopenia. Additionally, increased thrombopoietin degradation by platelets sequestered in the spleen may also contribute to thrombocytopenia in these patients.³⁶

TABLE 54.3 ABNORMALITIES OF HEMOSTASIS AND COAGULATION IN LIVER DISEASE

Deficient biosynthesis
	Of fibrinogen; prothrombin; coagulation factors V,³⁹ VII, IX, X, XI, XII, XIII; prekallikrein; high-molecular-weight kininogen Of antiplasmins,⁵⁸ antithrombin,⁵⁷ proteins C and S
Aberrant biosynthesis
	Of abnormal fibrinogen,⁴¹, ⁴⁵ factor V Of abnormal inhibitory analogs of prothrombin, factors VII, IX, and X⁴⁶
Deficient clearance
	Of hemostatic “products” (e.g., fibrin monomers, fibrin[ogen] degradation products, platelet factor-3) Of activated coagulation factors (IXa, Xa¹⁵⁸, XIa) Of plasminogen activators⁴⁹
Accelerated destruction of coagulation factors
	Disseminated intravascular coagulation⁶⁴, ⁶⁵, ⁶⁶ Abnormal fibrinolysis⁵⁰
Thrombocytopenia
	Hypersplenism (portal hypertension) Folic acid deficiency Chronic ethanol intoxication Disseminated intravascular coagulation
Platelet dysfunction
	Acute and chronic ethanol intoxication Effects of products of fibrinogen degradation⁵¹ Uremia
Miscellaneous
	Inhibition of coagulation by products of fibrinogen degradation⁵³, ⁵⁴ Loss or consumption of coagulation factors in ascitic fluid⁶⁸

Deficient or Aberrant Synthesis of Coagulation Factors

In patients with liver disease, all coagulation factors except factor VIII may be deficient as a consequence of synthetic failure of the hepatic cells. Failure of biosynthesis of coagulation factors often correlates with the severity of hypoalbuminemia, but exceptions to this rule are common. Deficiencies of prothrombin; factors VII, IX, and X; and proteins C and S result mainly from synthetic incompetence. For example, factor VII expression in liver biopsies from patients with liver disease decreases as the severity of hepatic dysfunction increases.³⁷ Impaired carboxylation of precursors may contribute to the defect.¹¹ Superimposed vitamin K deficiency may result from a poor diet or malabsorption caused by insufficient production of bile salts or by exocrine pancreatic insufficiency.³⁸ The failure of these coagulation abnormalities to respond to vitamin K administration provides good evidence of hepatic cell dysfunction.

Factors V, XI, and XIII are synthesized by the liver but are not vitamin K-dependent³⁹; all of these factors may be deficient in patients with severe liver disease. Plasma levels of factor XII, prekallikrein (Fletcher factor), and high-molecular-weight kininogen (Fitzgerald factor) also may be low in association with liver disease. Deficiencies of these latter three factors do not contribute to a bleeding diathesis.

Hypofibrinogenemia rarely may result from deficient hepatic biosynthesis³⁹, ⁴⁰ or may be the consequence of fibrinogenolysis or DIC, as discussed subsequently. In many patients with liver disease, prolongation of the thrombin time can be significant in the absence of hypofibrinogenemia or increased levels of fibrin(ogen) degradation products (FDPs).⁴¹ This apparently is the result of a qualitatively abnormal fibrinogen that is synthesized by the diseased hepatic cell. Such acquired dysfibrinogenemia has been reported in most forms of liver disease, ranging from mild acute hepatitis to acute hepatic necrosis and cirrhosis.⁴² Fibrin monomer polymerization is delayed,⁴³ and the abnormal fibrinogen molecule acts as an antithrombin.⁴¹ Additionally, this hepatic disease dysfibrinogen may have an abnormally high content of sialic acids⁴⁴ and may produce a structurally defective fibrin clot.⁴⁵ Acquired dysfibrinogenemia, abnormal inhibitors of fibrinolysis, and the presence within the plasma of descarboxy analogs of prothrombin⁴⁶ have been reported in patients with hepatomas.⁴⁷ Hepatoma-associated dysfibrinogens have also been noted to have an increased carbohydrate content.

Plasma levels of factor VIIIc usually are elevated in both parenchymal and cholestatic liver disease.⁴⁸ Studies in patients with cirrhosis indicate that elevated plasma factor VIII levels are not due to increased transcriptional activity of factor VIII in the liver, but instead likely result from increased liver synthesis of von Willebrand factor (vWF) and decreased levels of lipoprotein receptor-related protein. Both of these latter proteins regulate plasma factor VIII levels.⁴⁸

Fibrinogenolysis and Fibrinolysis

Endogenous plasminogen activators normally are removed from the circulation by the liver. In patients with severe liver disease, however, they may circulate for an abnormally long time and lead to the chronic or intermittent activation of the fibrinolytic enzyme system.⁴⁹, ⁵⁰ This process may be a contributory factor in the pathogenesis of hypofibrinogenemia in patients with liver disease. It also leads to the production of large amounts of FDP, which persist in the circulation for abnormally long periods because of deficient hepatic clearance, and may impair blood coagulation and platelet function.⁵¹ Such proteolytic activity also may produce a shift in the mean molecular weight of circulating fibrinogen from the normal species to a less reactive species of lower molecular weight,⁵² thereby contributing to the “antithrombins of liver disease.”⁵³, ⁵⁴

The incidence of hyperfibrinolysis was surveyed in patients with cirrhotic and noncirrhotic liver disorders.⁵⁵ Hyperfibrinolysis, as measured by a shortened euglobulin clot lysis time, was present in approximately 30% of cirrhotic patients but not present in noncirrhotic patients.⁵⁵ The role of thrombin-activatable fibrinolysis inhibitor deficiency in liver disease in contributing to hyperfibrinolysis has been studied; thrombin-activatable fibrinolysis inhibitor levels are reduced in liver disease, with lower levels seen in more severe liver disease.⁵⁶ However, there was no association of low thrombin-activatable fibrinolysis inhibitor levels with hyperfibrinolysis, even in cirrhotic patients. These studies suggest that hyperfibrinolysis is not common in liver disease, even in cirrhosis.⁵⁵, ⁵⁶

Plasma levels of antithrombin,⁵⁷ antiplasmin,⁵⁸ and plasminogen⁵⁹ are subnormal in patients with liver disease. These abnormalities are of uncertain clinical importance.

Intravascular Coagulation

Severe liver disease theoretically predisposes individuals to the development of DIC because DIC is associated with deficient hepatic clearance of activated coagulation factors and other coagulant substances. The in vivo turnover rates of prothrombin,⁶⁰ fibrinogen,⁶¹ plasminogen,⁶⁰ and antithrombin⁵⁷ often are accelerated in patients with cirrhosis. Plasma levels of fibrinopeptide A are elevated in most patients with cirrhosis.⁶² All of these abnormalities may be normalized in some cases by the administration of heparin.⁶³ It has been hypothesized that accelerated catabolism of coagulation factors in these disorders is the result of DIC. The nature of the initiating process is unclear, but one suggestion is that DIC is activated by hypoperfusion of the congested portal bed.⁴⁰ Indirect evidence suggests that in severe liver disease, activators of coagulation, possibly endotoxin, may originate in the gut.

Low-grade DIC or localized intravascular coagulation indeed may occur in association with severe liver disease, but overt DIC is responsible only rarely for bleeding in the absence of other etiologic factors that trigger this process, for instance, sepsis, shock, and cancer.⁶⁴, ⁶⁵ This conclusion is supported by findings in patients with stable cirrhosis that demonstrated no increased levels of markers of activation of coagulation, such as prothrombin fragment 1+2, thrombin-antithrombin complex, and so forth.⁶⁶

Evidence for accelerated fibrinogen turnover in ascitic fluid suggests that the loss or consumption of coagulation factors in peritoneal fluid may be a contributory factor in the coagulopathy of chronic liver failure. Shunting of ascitic fluid into the venous circulation by means of LeVeen shunts consistently produces coagulation abnormalities consistent with DIC in cirrhotic patients.⁶⁷ Although this phenomenon usually is attributed to intravascular coagulation, evidence shows that it may result in part from the presence of plasminogen activators and active plasmin⁶⁸ or collagen⁶⁹ in peritoneal fluid.

A transitory coagulation disorder that resembles intravascular coagulation with active fibrinolysis has been documented during liver transplantation procedures. Coagulation abnormalities disappear promptly if the graft is successful.⁷⁰ The complex coagulopathy seen with liver transplantation has been reviewed.⁷¹

Clinical Manifestations

In view of the numerous hemostatic abnormalities associated with severe liver disease, it is surprising that many patients do not bleed abnormally. Gastrointestinal hemorrhage is the most common bleeding manifestation, but it almost always originates from a local lesion, such as esophageal varices, peptic ulcer, or gastritis. The degree to which coagulation abnormalities contribute to such bleeding is uncertain. In one large series, gastrointestinal bleeding was not significantly more severe or protracted in patients with coagulation abnormalities than in those without them.⁷² In another study, serious hemorrhage occurred only in patients with prolonged PTs and significant factor IX deficiency.⁷³ Moderate generalized bleeding manifestations, such as recurrent ecchymoses and epistaxis, are not uncommon, and severe generalized bleeding may complicate surgical procedures, including biopsies, tooth extractions, and other minor procedures.

The above-mentioned paradox of the lack of bleeding in many patients with severe liver disease despite multiple hemostatic abnormalities has been explored.⁷⁴ An emerging concept is that coagulation in liver disease patients is “rebalanced” due to parallel reductions in both procoagulant and anticoagulant factors. Standard coagulation tests (such as the PT) do not measure major in vivo regulators of coagulation such as thrombomodulin and may not adequately reflect hemostasis in these patients.³², ⁷⁴ This new paradigm has implications for managing the coagulopathy of liver disease.

Laboratory Diagnosis

The laboratory findings in liver disease vary with the cause and severity of the underlying disorder and range from a slight prolongation of the PT in anicteric hepatitis to the findings summarized in Table 54.2, which are seen in severe decompensated cirrhosis. In cirrhosis, coagulation abnormalities correlate with the presence of portal hypertension and may be minimal in inactive cirrhosis; thrombocytopenia alone is common in association with portal hypertension. Acute fibrinogenolysis is significantly more common in patients with cirrhosis⁵⁵ than in those with acute hepatocellular disease, such as hepatitis, although elevations of FDP are consistently found in people with chronic aggressive hepatitis.⁴² Coagulation abnormalities are seldom marked in biliary cirrhosis, and some patients with this disorder have abnormally high levels of prothrombin and factors VII and X. Hemostatic abnormalities of any sort are rare in metastatic liver disease. In acute liver failure, the PT value has prognostic value and is indicative of the need for liver transplantation.⁷⁵ The spectrum of coagulation abnormalities in liver disease has been reviewed.³¹

Although screening tests of coagulation are almost invariably performed before liver biopsy, they apparently are of little value in predicting hemorrhage after this and other minor surgical procedures.³², ⁷⁴, ⁷⁶, ⁷⁸ Similarly, the bleeding time test is of little clinical use in predicting bleeding.⁷⁹ Many physicians use the international normalized ratio (INR) as a substitute coagulation test for the PT.⁸⁰ When measured with a sensitive thromboplastin, the INR can quantitate vitamin K deficiency due to liver disease, but it should not be interpreted as in patients receiving warfarin.⁸⁰

Treatment

Not all patients with the coagulopathy of liver disease require hemostatic correction before procedures such as liver biopsy. A retrospective study looked at the PT ratio (patient PT/mean of reference range PT) and degree of thrombocytopenia to determine the necessity of plasma and platelet transfusion.⁸¹ In patients with platelet counts of 50,000/µl or greater, there was no increased bleeding with liver biopsy compared with patients with normal platelet counts. With regard to elevated PT values, if the PT ratio was <1.5, no increased bleeding was observed.⁸¹ Therefore, patients with moderate thrombocytopenia and mild liver disease coagulopathy do not need routine hemostatic correction with blood products. One exception to this recommendation is patients with a diagnosis of malignancy, who may have a higher bleeding risk, possibly due to chronic DIC and elevated FDP levels.⁸¹ On the other hand, a British guidelines committee on the use of plasma products suggests that “patients with liver disease and a PT more than 4 seconds longer than control are unlikely to benefit from FFP.”⁸² This recommendation is based on expert opinion.

Elevated FDP levels may be a significant hemostasis risk factor in liver disease. High levels of FDP may impair platelet function and fibrin monomer polymerization. The thrombin time can screen for the latter defect. A prolonged thrombin time in a patient with a normal functional fibrinogen level and high FDP levels, who is not receiving heparin, may constitute a significant bleeding risk, especially in the setting of moderate thrombocytopenia.

Vitamin K₁, in a dose of 10 mg, produces some improvement in the coagulation abnormalities in approximately 30% of patients with liver disease,⁷³ but the PT often becomes prolonged again after an initially favorable response. Patients with severe liver disease have minimal or no response to vitamin K therapy.

Replacement therapy with fresh frozen plasma is indicated only in the presence of serious bleeding or before surgical procedures, and its effect is often disappointing in patients with liver disease.⁷³ Reasons for this may include the short in vivo half-life of factor VII, hypervolemia, the loss of transfused factors into ascitic fluid, and the fact that the in vivo recovery of transfused factor IX is significantly lower than that of other factors, even in the absence of liver disease. Concentrates of vitamin K-dependent coagulation factors (PCC) have been used in the replacement therapy of bleeding in patients with liver disease with variable success but, in several cases, have led to thromboembolic complications and DIC.⁸³ Thrombosis presumably develops because such concentrates contain trace amounts of activated coagulation factors, particularly factors IXa and Xa,⁸³, ⁸⁴ that normally are not cleared from the circulation by the diseased liver and because of antithrombin deficiency, which is commonly present. Newer PCCs are becoming available; these also contain proteins C and S in addition to the procoagulant vitamin K-dependent factors. These products have not been well studied in liver disease coagulopathy, but appear to be effective in reversing warfarin coagulopathy.⁸⁵ Fresh frozen plasma is the preferable treatment option, but the effects of even maximum doses (20 to 30 ml/kg of body weight) often are transitory. Cryoprecipitate is useful to maintain fibrinogen levels over 100 mg/dl. A controlled trial found that 1-desamino-8-darginine vasopressin (DDAVP) is not helpful in management of variceal bleeding in cirrhotic patients.⁸⁶

Recombinant factor VIIa (rVIIa) is a potential therapy for liver disease patients with significant coagulopathy. However, the drug is not indicated for use in variceal bleeding, partial hepatectomy, or liver transplantation.⁸⁷ Disadvantages of rVIIa include its high cost and risk of DIC and thromboembolic complications.

Even though heparin administration may normalize fibrinogen catabolism, little evidence is cited that it decreases the duration or severity of bleeding in patients with low-grade DIC and severe liver disease. However, heparin may be useful in conjunction with PCC therapy. In this setting, the addition of small amounts of normal plasma and heparin to vials of these thrombogenic concentrates inactivates activated proteases and minimizes the thrombotic risks of these concentrates.⁸⁸

Correction of thrombocytopenia may be difficult in patients with severe liver disease. One promising intervention is the use of synthetic thrombopoietins and thrombopoietin mimetic agents. Eltrombopag is approved to treat thrombocytopenia in chronic hepatitis C patients who receive interferon therapy.

For patients requiring liver biopsy who are deemed “high risk” from the hemostasis perspective, the transjugular approach should be considered.

DISSEMINATED INTRAVASCULAR COAGULATION

The syndrome of DIC (defibrination syndrome, consumption coagulopathy) has been one of the most intensively studied subjects in hematology. This large body of information has been summarized in many detailed reviews and monographs.⁸⁹, ⁹⁰, ⁹¹ A consensus definition of DIC has been proposed: “DIC is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction.”⁹⁰

Etiology and Incidence

DIC has been well documented in association with the disorders summarized in Table 54.4. Several retrospective studies suggest that DIC remains a relatively uncommon entity, but in one large general hospital, its overall incidence was 1 in 1,000 admissions.⁹² The most prevalent etiologic factor was infection,⁹² but in another study, more than 50% of cases were obstetric patients.⁹³ A Japanese study found that in a hospital population, 45% of DIC cases were associated with malignancy.⁹⁴ In many of the disorders listed in Table 54.4, DIC develops only in an occasional case. Thus, it is rare in heatstroke,⁹⁵ autoimmune disorders,⁹⁶ and hemolytic anemias.⁹⁷ DIC is present in most cases of venomous
snakebite, which is probably one of the most common causes of the disorder worldwide.

TABLE 54.4 ETIOLOGIES OF DISSEMINATED INTRAVASCULAR COAGULATION

Obstetric complications
	Abruptio placentae,¹⁸⁸ septic abortion and chorioamnionitis, amniotic fluid embolism, intrauterine fetal death, miscellaneous (degenerating hydatidiform moles and leiomyomas, postpartum hemolytic-uremic syndrome, abdominal pregnancy, tetracycline-induced hepatorenal failure, fetomaternal blood passage, saline-¹⁹⁴ and urea-induced¹⁹⁵ abortions)
Infections
	Viral (herpes, rubella, smallpox, acute hepatitis, Reye syndrome, cytomegalic inclusion disease, various epidemic hemorrhagic fevers, others) Rickettsial (Rocky Mountain spotted fever, others) Bacterial (meningococcemia, septicemia, particularly that due to Gram-negative organisms, many others) Mycotic (histoplasmosis, aspergillosis) Protozoal (malaria, kala-azar, trypanosomiasis)
Neoplasms
	Carcinomas⁹⁸ (prostate, pancreas, breast, lung, ovary, many others) Miscellaneous (metastatic carcinoid, rhabdomyosarcoma, neuroblastoma, others)
Disorders of the hematopoietic system
	Acute leukemia (promyelocytic²¹⁹, other types) Intravascular hemolysis (transfusion of incompatible blood, paroxysmal nocturnal hemoglobinuria⁶⁰⁷, fresh-water submersion⁶⁰⁸) Histiocytic medullary reticulosis
Vascular disorders
	Malformation (giant hemangiomas [Kasabach-Merritt syndrome]²²⁵, aneurysms, coarctations of the aorta and other large vessels, Takayasu aortitis, large prosthetic arterial grafts,⁶⁰⁹ cyanotic congenital cardiac lesions) Collagen-vascular disorders⁶¹⁰ Hypoxia and hypoperfusion, myocardial infarction, cardiac arrest,⁶¹¹ various forms of shock, hypothermia
Massive tissue injury
	Large traumatic injuries and burns, extensive surgical intervention,⁶¹² extracorporeal circulation, fat embolism⁶¹³
Miscellaneous
	Acute iron toxicity, head trauma,⁶¹⁴ snakebite,²³¹ anaphylaxis, concentrates of vitamin K-dependent coagulation factors,⁸³ heatstroke,⁹⁵ allograft rejection, graft versus host disease, severe respiratory distress syndrome, diabetic acidosis,⁶¹⁵ status epilepticus,⁶¹⁶ acute pancreatitis,⁶¹⁷ homozygous deficiency of protein C⁶¹⁸

Pathophysiology

Mechanisms by Which Disseminated Intravascular Coagulation Is Initiated

The pathophysiology of DIC is complex. The mechanisms that activate or “trigger” DIC act on processes that are involved in normal hemostasis, namely, the processes of platelet adhesion and aggregation and contact-activated (intrinsic) and tissue factor-activated (extrinsic) pathways of coagulation (Fig. 54.2). These mechanisms have in common the capacity, in terms of either the magnitude or the duration of the activating stimulus, to exceed normal compensatory processes. Thrombin is persistently generated, and fibrin is formed in the circulating blood. Fibrinogen, various other coagulation factors, and platelets are consumed. The fibrinolytic mechanism is activated, and large amounts of FDP are produced, which further impair hemostatic function. Bleeding, shock, and vascular occlusion commonly supervene and produce profound alterations in the function of various organ systems. Normal compensatory processes may become impaired, creating a selfperpetuating “vicious cycle.” The ultimate outcome is determined by a dynamic interplay between the various pathologic processes and compensatory mechanisms, in other words, fibrin deposition versus fibrinolysis; depletion versus repletion of coagulation factors and platelets; and production versus clearance of fibrin, FDPs, and other products of coagulation (Fig. 54.3). In most forms of DIC, the initiating factors are multiple and interrelated. For example, in meningococcemia, endothelial cell injury may lead to expression of tissue factor and to collagen exposure; the latter then initiates platelet adhesion, aggregation, and thrombosis.

FIGURE 54.2. Initiating mechanisms of disseminated intravascular coagulation (DIC). The solid arrows indicate normal hemostatic pathways, and dotted arrows indicate pathways by which certain disorders associated with DIC initiate or promote the coagulopathy of DIC. Initiation of coagulation by expression of tissue factor activity is probably the most important mechanism triggering DIC.

Tissue Factor

The exposure of procoagulant tissue extracts to blood is a major contributory factor in most forms of DIC and is of major pathogenetic importance in cases associated with abruptio placentae, intrauterine fetal death, acute promyelocytic leukemia, amniotic fluid embolism, massive trauma, and various neoplasms.⁹⁸ The active component of such extracts is tissue factor (thromboplastin); that is, tissue factor interacts with factor VIIa to activate the extrinsic pathway of coagulation.

In abruptio placentae⁹⁹ decidual fragments, serum-containing activated coagulation factors, and other substances from the placental site enter the intervillous “maternal lake” and, hence, the venous circulation. This process is initiated by rupture of the basal decidual plate.

In amniotic fluid embolism, relatively weak thromboplastins that increase in potency with gestational age¹⁰⁰ and large
amounts of particulate matter enter the circulation suddenly. In intrauterine fetal death, thromboplastic substances from the dead fetus are slowly but continuously absorbed, producing a picture of chronic but progressive DIC.

FIGURE 54.3. Pathophysiology of disseminated intravascular coagulation (DIC). The critical event in DIC is the generation of thrombin in an unregulated fashion. The clinical consequences of thrombin production depend on the rate of thrombin formation as well as underlying host factors (marrow reserve of platelet production, liver function). Patients with adequate compensatory responses (ability to enhance platelet or coagulation factor production, fibrinolysis, intact clearance mechanisms) may have minimal symptoms, whereas other patients with defective compensatory responses may bleed, thrombose, or both. Increased levels of cytokines occur (TNF, IL-1) that contribute to the proinflammatory state by down-regulating thrombomodulin activity; this leads to enhancement of intravascular fibrin formation and organ dysfunction. Major compensatory factors that influence clinical events are indicated in colored blocks. The zig-zag line indicates interruption of an adverse clinical event by a compensatory factor. FDP, fibrin(ogen) degradation product; IL-I, interleukin-1; PAI-1, plasminogen activator inhibitor-1; TNF, tumor recrosis factor.

In neoplasms, tumor microemboli and tumor “vesicles”¹⁰¹ are thought to enter the circulation and act as thromboplastins.⁹⁸, ¹⁰² Tumor cell surface expression of tissue factor has been demonstrated.¹⁰³ Some neoplasms may secrete a factor X activator.¹⁰⁴

DIC in association with acute leukemia presumably results from the formation or release of tissue factor by leukemic cells.¹⁰⁵ Additional leukocyte enzymes such as elastase may contribute to DIC and fibrin(ogen)olysis by proteolysis of coagulation zymogens and fibrinogen.¹⁰⁶ Malignant promyelocytes, as seen in promyelocytic leukemia, express high levels of annexin II, a phospholipid-binding protein and receptor for plasminogen and tissue plasminogen activator.¹⁰⁷ This overexpression of annexin II results in enhanced plasmin production and increased fibrinolytic activity.¹⁰⁷ The granules of various “blast” forms contain tissue factor, with the promyelocyte containing particularly high concentrations.¹⁰⁵

In DIC associated with massive trauma,¹⁰⁸ major surgical procedures, or large burns, damaged tissue expressing tissue factor activity presumably is a major initiating factor. In such cases, additional abnormalities and complications are important contributory factors, such as “hypercoagulability,” azotemia, shock, intravascular hemolysis, massive transfusions of stored blood, septicemia, and hypoxia. Cerebral trauma of sufficient magnitude to produce significant brain destruction induces a brief episode of DIC, which, although transitory, may be significant in that it may perpetuate cerebral bleeding.¹⁰⁹

Monocyte-associated Procoagulants

It has been known for many years that monocytes and tissue macrophages may, when suitably activated, express substances capable of initiating blood coagulation.¹¹⁰ This phenomenon is thought to be of importance in inflammation and in tissue localization of infectious agents and tumors. It has become apparent that “recognitioncoupled” responses of the monocyte-macrophage system¹¹¹ may be important in triggering DIC in association with meningococcemia¹¹² and other forms of septicemia, certain forms of leukemia, major transfusion reactions, and anaphylaxis. The best defined model of this process is the induction of tissue factor by monocytes exposed to endotoxin¹¹³ or immune complexes.¹¹⁴ Other substances that may induce monocyte procoagulant activity include anaphylatoxins¹¹⁵ and cytokines.¹¹⁶ Most of these substances induce the formation of monocyte coagulants only in the presence of T lymphocytes¹¹⁷ and the complement system.¹¹⁵ A prothrombinaselike activity¹¹⁸ and a specific activator of factor X¹¹⁹ also are formed by appropriately conditioned monocytes.

Vascular Endothelium

In addition to monocytes or macrophages, vascular endothelium can be induced to express tissue factor activity in the setting of experimental DIC.¹²⁰ Endothelium can also be down-regulated in
terms of anticoagulant properties (e.g., thrombomodulin activity, fibrinolysis) by stimuli relevant in the pathogenesis of DIC (see Chapter 19). This altered endothelium is referred to as activated; properties of activated endothelium include conversion of the normally anticoagulant phenotype to a procoagulant phenotype, expression of adhesion molecules, production of inflammatory mediators, and production of vasoactive agents.¹²¹ Many of these pathologic events are amplified by endothelial cell proteaseactivated receptors (PARs) (see Chapter 19). Vascular endothelium may also promote coagulation by formation of thrombogenic microparticles, which express anionic phospholipid.¹²² Microparticles in DIC may also originate from platelets or granulocytes.¹²³ Thrombin generation caused by activation of factor XII in DIC appears to be less important than that initiated by tissue factor.¹²⁴ Contact activation, instead, appears critical in mediating DIC-associated hypotension.¹²⁵

Role of Cytokines

Although there are numerous etiologies for DIC (Table 54.4), a common pathway for activation of coagulation by these disorders is cytokine release.⁸⁹ Important mediators include endotoxin, interleukin-1 (IL-1), IL-6, IL-8, platelet activating factor, and tumor necrosis factor (TNF). TNF and IL-1 both increase monocyte and endothelial cell tissue factor activity and inhibit protein C activation. Elevated levels of IL-8 correlate with sepsis mortality and DIC.¹²⁶

Infections

DIC often accompanies septicemia as a result of bacteria that possess potent endotoxins. This correlation has led to the intensive study of the effects of endotoxin on the hemostatic mechanism. Purified endotoxin produces several effects that may lead to DIC, namely, activation of factor XII,¹²⁷ platelet aggregation, inhibition of fibrinolysis, leukocyte aggregation, direct endothelial injury,¹²⁸ cellular induction of tissue factor activity,¹²⁹ and impairment of compensatory clearance functions. Many of these phenomena may be mediated by the interaction between endotoxin and monocytes, as discussed earlier.

Shock, Hypoperfusion, and Hypoxemia

Shock may favor the development of DIC by potentiating various activating stimuli that ordinarily would not exceed the capacity of compensatory processes and may perpetuate DIC after a transient activating stimulus has been dissipated. Hypoperfusion, even of normal vessels, acidosis, and hypoxemia produce hypercoagulability and favor intravascular platelet aggregation. Furthermore, splanchnic hypoperfusion impairs reticuloendothelial and hepatic clearance functions and is present in virtually all forms of shock. Shock also may impair hepatic synthesis of coagulation factors and thus contribute to the coagulation defect in DIC. Activated neutrophils may generate oxygen radicals and proteases to alter vascular permeability. Vascular injury may also occur with ischemia/reperfusion that elicits inflammatory responses.

DIC in association with giant hemangiomas (Kasabach-Merritt syndrome)¹³⁰ or with aneurysms of the aorta or other large vessels¹³¹ has been attributed to hypoperfusion and stasis in local vascular beds. In Kasabach-Merritt syndrome, large gaps in the endothelium that expose subendothelial collagen and other fibers, together with the induction of thromboplastic substances by poorly supported, recurrently injured vessels within the tumor, also may be important factors leading to the initiation of DIC.

Miscellaneous Activating Stimuli

Snake venoms contain enzymes that may trigger coagulation in unique ways. Such venoms may produce defibrination without affecting other coagulation factors, such as ancrod, an enzyme purified from the venom of the Malayan pit viper (Agkistrodon rhodostoma). Other venoms contain thrombinlike enzymes or substances that specifically activate factor X or prothrombin.¹³² Crude venoms also contain substances that act as thromboplastins and produce intravascular red cell hemolysis and massive vascular damage.¹³³ An inventory of the biochemical properties of snake venoms and their constituent enzymes has been summarized elsewhere.¹³⁴, ¹³⁵

Consumption of Coagulation Factors and Impaired Anticoagulant Pathways

DIC constitutes a model of accelerated turnover of various coagulation factors, the levels of which at any time are determined by the size of the plasma pool and the differences between the rates at which they are being destroyed and replenished. Results of quantitative studies have demonstrated accelerated turnover rates for platelets, fibrinogen,¹³⁶ and prothrombin. Numerous factors complicate a simple kinetic approach. For example, the depletion of plasma fibrinogen induces a compensatory release of large amounts of fibrinogen into the circulation, possibly from the hepatic-lymphatic system, and also increases the rate of fibrinogen synthesis. Other complexities include impaired hepatic synthesis of coagulation factors and the phenomenon of postdepletion “rebound” and “overshoot.”¹³⁷

Generalizations based on the consumption of coagulation factors during in vitro coagulation are not always consistent with laboratory findings in patients with DIC. Plasma levels of factors that are normally consumed, such as fibrinogen, prothrombin, and factors V and XIII, often are reduced in severe DIC, but factors that normally are not consumed also may be deficient, such as factors VII, IX, and X. Prothrombin, which is consumed completely during coagulation in vitro, often is at a normal level in patients with DIC. Significant hypoprothrombinemia must reflect either massive and protracted activation of coagulation or complicating factors, because in animals, severe depletion of platelets, fibrinogen, and factors V and VIII results from activation of only 10% of plasma prothrombin.¹³⁸

Proteins other than coagulation factors may be depleted as a result of DIC; those of potential importance include antithrombin,¹³⁹ α₂-antiplasmin,¹⁴⁰ and plasminogen.¹⁴¹ Plasminogen has great avidity for fibrin and may co-precipitate in fibrin thrombi. In experimental animals, depletion of tissue plasminogen activator, as well as plasminogen, can be produced by the protracted infusion of tissue factor.

Antithrombin is the principal inhibitor of thrombin activity; low levels of antithrombin in DIC result from consumption due to persistent neutralization of thrombin, degradation by elastase released from activated neutrophils, and decreased hepatic synthesis. Other natural anticoagulant pathways—the protein C pathway and tissue factor pathway inhibitor—are also diminished in DIC.¹⁴² Proinflammatory cytokines (TNF, IL-1) down-regulate endothelial cell thrombomodulin activity, resulting in decreased levels of activated protein C (APC). Low levels of APC not only fail to inhibit activation of coagulation (by inactivating factors V_a and VIII_a), but also contribute to failure to down-regulate inflammation. Thus, impairment of the protein C pathway in DIC contributes to the procoagulant and inflammatory phenotype seen in the disorder.

The numerous and diverse defense processes that are mediated by factor XIIa are activated in DIC, including the complement system and the kallikrein system. It has been suggested that the hypotensive effects of bradykinin may explain the conspicuous presence of hypotension in patients with DIC triggered by activation of factor XII,¹⁴³ for example, that associated with endotoxemia.

Consumption of Platelets

In DIC, the platelet count often is depressed out of proportion to the severity of coagulation abnormalities. Thrombocytopenia may result from processes other than the consumption of platelets in
thrombotic lesions. These processes include adhesion to denuded or damaged endothelial cell surfaces and intravascular aggregation with subsequent sequestration, which may be caused by endotoxin, antigen-antibody complexes, thrombin, particulate matter, and, possibly, fibrin-FDP complexes.

All of these agents initiate the platelet release reaction, which may produce a population of partially activated platelets that are depleted of storage nucleotides (acquired storage pool disease). Partially activated platelets may contribute to impairment of clearance functions. Epinephrine and serotonin are released from the platelets and may reach extremely high concentrations in hypoperfused vascular beds. This process may produce sustained constriction of the afferent renal arteriole and may predispose to cortical necrosis. Serotonin also may produce pulmonary and cerebral hypoperfusion.

A mouse model of DIC investigated the role of PARs in mediating the endothelial cell and platelet response to activation of coagulation. In this model of endotoxemia, activation of coagulation occurred, but knockout of PARs failed to improve survival or thrombocytopenia. Although this model may not be extrapolated to human DIC, the possibility is suggested that PARs may not mediate the DIC response, and that thrombocytopenia in DIC may result from mechanisms other than thrombin activation.¹⁴⁴

Intravascular Fibrin Formation

The formation of fibrin, in the form of small strands and “microclots”, is the immediate result of DIC; the ultimate consequence of this process is determined by a balance between the rate of fibrin formation and the rate of its clearance from the circulation or lysis by the fibrinolytic enzyme system.

Erythrocytes are injured mechanically during passage through fibrin networks in the microcirculation. Such microangiopathic hemolysis leads to the production of schistocytes and microspherocytes. Erythrocyte damage in metastatic carcinoma appears to be caused mainly by fibrin strands that form around tumor cell emboli as a result of low-grade DIC.¹⁴⁵ It should be noted that red cell fragmentation is not seen in all patients with DIC.¹⁴⁶

Fibrinolysis

Fibrinolysis is present in virtually every patient with DIC, but it generally plays a homeostatic rather than a pathologic role. In the setting of DIC, this “secondary fibrinolysis” is an appropriate response to persistent thrombin generation. Fibrinolysis may be activated by several mechanisms. The major endogenous source of plasminogen activators is in the vascular endothelium of the microcirculation, and in DIC, such activators, especially tissue plasminogen activator, are apparently released as a result of thrombin formation and fibrin deposition on endothelial surfaces, endothelial injury, or hypoxia. Many of the thromboplastic substances that initiate DIC, such as tumor tissues and extracts of leukemic cells, also contain plasminogen activators. The release of plasminogen activators from platelets and leukocytes also may be significant. Finally, factor XIIa activates plasminogen by interacting with normal proactivators and the kinin system.¹⁴⁷

Fibrinolysis must be distinguished clearly from the process of fibrinogenolysis, in which fibrinogen and other coagulation factors are proteolytically destroyed in the circulation. Fibrinogenolysis may be an inappropriate response in DIC associated with amniotic fluid embolism,¹⁴⁸ heatstroke,⁹⁵ and, rarely, carcinoma. It is uncommon in other forms of DIC; when present, it is usually transitory and overshadowed by marked fibrinolysis. Disorders in which fibrinogenolysis arises in the absence of DIC (primary fibrinolysis) are discussed elsewhere in this chapter.

Following the initial enhanced fibrinolytic response to DIC, suppression of fibrinolysis occurs due to elevated levels of plasminogen activator inhibitor-1; this inhibition of fibrinolysis was associated with a poorer clinical outcome.¹⁴⁹

Fibrin(ogen) Degradation Products

The stepwise process by which fibrin is degraded proteolytically and the biologic effects of the various products of the process (FDPs) are discussed in Chapter 18. These protein fragments act as antithrombins,⁵³, ⁵⁴ inhibit fibrin polymerization, produce a structurally defective fibrin polymer,¹⁵⁰ and may impair platelet⁵¹ and reticuloendothelial clearance functions. The presence of large amounts of FDP in the circulation is a major factor in the production of hemorrhage in many patients with DIC.

The infusion of large amounts of FDP (fragment D) into rabbits produces changes that resemble the posttraumatic respiratory distress syndrome in humans.¹⁵¹ This observation suggests that large amounts of FDP may directly damage the pulmonary vasculature, leading to respiratory distress syndrome, which has been reported in association with DIC and the use of thrombolytic agents.¹⁵² The smallest FDPs are peptides of 3,000 to 4,000 molecular weight that inhibit smooth muscle contractility, an effect that may explain the frequency of uterine inertia in abruptio placentae.¹⁵³

In DIC, a large amount of fibrin remains in a soluble state as a consequence of the formation of complexes between fibrin monomers, various FDPs, and fibrinogen. This solubility has been regarded as a final defense against vascular occlusion. In vitro, the complexes dissociate in the presence of alcohol or protamine sulfate to form gels or precipitates of various types (paracoagulation).

Impairment of Clearance Mechanisms

The numerous processes that normally remove procoagulant material from the circulation are of the utmost importance in DIC because of the presence of massive amounts of both activators and products of coagulation. Most of the products of intravascular coagulation (prothrombinase, platelet factor-3 activity, various types of FDPs and complexes thereof¹⁵⁴, ¹⁵⁵), as well as various initiators of the process (tissue fragments, endotoxin, antigenantibody complexes, tissue factor, and red cell stroma), are removed from the circulation by the reticuloendothelial system¹⁵⁶ (Fig. 54.3). The Kupffer cells of the liver¹⁵⁷ and splenic macrophages are of particular importance. In certain forms of DIC, large amounts of relatively inert particulate matter (e.g., amniotic fluid embolism) place an additional burden on the reticuloendothelial system. The hepatic cells are of primary importance in the clearance of activated coagulation factors (IXa, Xa,¹⁵⁸ and XIa).

Investigators have suggested that various substances saturate and produce an “autoblockade” of reticuloendothelial and hepatic clearance functions in DIC in a manner comparable to that produced experimentally in the Shwartzman reaction.¹⁵⁶, ¹⁵⁹ This blockade may be an important pathophysiologic factor, particularly in perpetuating DIC after a transient activating stimulus. Shock and endotoxemia, both of which produce significant hepatic hypoperfusion, may contribute indirectly to autoblockade of clearance functions.

Chronic or “Compensated” Disseminated Intravascular Coagulation

Certain forms of DIC result from a weak or intermittent activating stimulus. In such patients, destruction and production of coagulation factors and platelets are balanced (Fig. 54.3). The pathophysiology of such chronic, subacute, or “compensated” DIC is fundamentally the same as that in the acute case. Nevertheless, the distinction is valuable because the clinical picture and laboratory findings in the chronic form are quite variable and may be diagnostically confusing.

Chronic DIC has been described in many patients with intrauterine fetal death or giant hemangiomas (Kasabach-Merritt syndrome) and in many cases of adenocarcinoma.⁹⁸ Other etiologic factors that may produce chronic DIC include various forms of vasculitis, acute leukemia, aneurysms, hemangiomatous transformation of the spleen, and renal allograft rejection.

In cancer patients, a virtually continuous spectrum of clinical and laboratory features has been described; these range
from recurrent venous thrombosis or arterial embolism⁹⁸ with high levels of platelets and coagulation factors to acute DIC with severe hemorrhage.⁹⁸ The clinical and experimental evidence is incontrovertible that pregnancy, the best studied form of hypercoagulability, is associated with an increased propensity for the development of DIC.¹⁶⁰, ¹⁶¹ Indeed, even normal pregnancy has been suggested as a form of low-grade “physiologic” DIC,¹⁶⁰ which, at term, becomes overt for a short time. Thus, transitory but significant elevations of FDP and corresponding diminution in fibrinogen levels are observed regularly during the first 4 hours after delivery.¹⁶⁰ This may be triggered, in part, by the release of tissue factor into the circulation.

Clinical Features

The major clinical features of DIC are bleeding, often of serious magnitude and abrupt onset; a variable element of shock that is often out of proportion to apparent blood loss; and symptoms of hypoperfusion of various vascular beds. Acute renal failure is common, and thromboembolic manifestations often are noted.¹⁶² Any of these features or signs and symptoms of the underlying disorder may predominate in a given case.

Evidence of major organ dysfunction is a common finding in patients with DIC, most often including signs, symptoms, and laboratory evidence of abnormal pulmonary, renal, hepatic, and central nervous system function. Although virtually all of these manifestations have been attributed to the underlying DIC, the clinical manifestations that have been described usually were the result of the underlying disorder. For example, one study observed that patients with DIC due to aortic aneurysm had laboratory features of DIC but minimal clinical manifestations. Patients with DIC due to obstetric disorders all had bleeding, but only 20% had organ dysfunction. In contrast, of patients with DIC due to sepsis, only 15% had bleeding, but 76% had organ failure.⁹⁴ These results suggest that marked heterogeneity exists in clinical manifestations of DIC, and that the etiology of DIC is a major predictor of clinical events.⁹⁴

In this section, the clinical manifestations and diagnosis of DIC are discussed in general terms. Various specific clinical features and details regarding treatment of the most common forms follow in a separate section.

Acute Disseminated Intravascular Coagulation

Bleeding manifestations of virtually every kind have been described, and they may evolve rapidly in the patient with acute DIC. Generalized ecchymoses, petechiae, and bleeding from previously intact venipuncture sites or around indwelling intravenous needles or catheters are noted in many patients. Large, spreading, hemorrhagic skin lesions often are superimposed on familiar exanthems in patients with rickettsial and viral infections. “Geographic” acral cyanosis is a prominent feature in some patients. Large, sharply demarcated ecchymotic areas may result from thrombotic occlusion of dermal vessels and may progress to skin infarction. Such infarcts are particularly common in patients with purpura fulminans (Fig. 54.4) and are seen also in coumarininduced skin necrosis and inherited homozygous deficiency of protein C (see Chapter 55). In patients with meningococcemia, cutaneous hemorrhage may be striking. Bleeding from apparently normal gingivae, epistaxis, gastrointestinal bleeding, pulmonary hemorrhage, and hematuria are common. In patients who develop DIC after surgical procedures, alarming hemorrhage may develop around drains and tracheostomies, and accumulations of blood may be concealed in serous cavities.

Chronic Disseminated Intravascular Coagulation

Superficial but extensive ecchymoses of the extremities, often without petechiae, may develop intermittently or may persist. Recurrent episodes of epistaxis or more serious internal mucosal bleeding may punctuate the course. Trousseau sign (recurrent migratory thrombophlebitis in association with cancer) in most instances is a manifestation of chronic DIC. More serious hemorrhagic manifestations may develop as the underlying disease progresses or may arise with dramatic suddenness after surgical procedures such as a prostatectomy. Acute DIC may be heralded by further thrombophlebitis or pulmonary emboli. In some patients, evidence of vascular obstruction (e.g., impairment of renal function, confusion, transitory neurologic syndromes, or repeated episodes of cerebral thrombosis) may develop with minimal bleeding.

FIGURE 54.4. Purpura fulminans in infection-associated disseminated intravascular coagulation. Early lesions (A) are circumscribed; progressive lesions (B) may become necrotic. (From Dudgeon DL, Kellogg DR, Gilchrist GS, et al. Purpura fulminans. Arch Surg 1971;103: 351-358; copyright 1971, American Medical Association.)

Laboratory Diagnosis

The laboratory findings in DIC are summarized in Table 54.2. Contrary to what is commonly assumed, they may be quite variable. The plasma fibrinogen level, PTT, PT, platelet count, and estimates of FDP or D-dimer are the cornerstones on which the diagnosis of DIC is based. These simple tests should always be performed first. Additional information may confirm, but seldom refutes, the diagnosis of DIC if typical abnormalities are demonstrated by these tests. Laboratory data may change with remarkable rapidity in DIC, based on disease progression or therapy.

Laboratory data must be interpreted with caution. Levels of platelets and various coagulation factors, fibrinogen, and factor VIII, in particular, may be elevated in many of the conditions associated with DIC, including pregnancy. Thus, a fibrinogen level of 200 mg/dl, although within the normal range determined in
healthy subjects, may represent a significant decrease in a patient whose baseline level was 800 mg/dl due to acute-phase changes.

The best test for diagnosing DIC is the D-dimer assay. The semiquantitative method is sensitive,¹⁶³ and D-dimer values >2,000 ng/ml have been reported to be consistent with DIC.¹⁶⁴ More sensitive, quantitative D-dimer assays are now available; one study reported that a sensitive D-dimer assay result <8.2 µg/ml optimized sensitivity and negative predictive value in patients with DIC.¹⁶⁵

A new test, measurement of the biphasic waveform in the PTT assay, has been reported to precede development of DIC and to predict DIC better than the D-dimer assay.¹⁶⁶ The biphasic waveform results from the formation of a precipitate on plasma recalcification; the precipitate contains very-low-density lipoprotein complexed with C-reactive protein. If confirmed in clinical outcome studies, this assay may be a useful addition to laboratory tests for DIC.

Basic Blood Examinations

In patients with DIC, routine hematologic tests may reveal evidence of acute bleeding, accelerated red cell destruction, or signs of the underlying disease. Examination of the blood smear reveals schistocytes in approximately 50% of cases,⁹³, ¹⁴⁶ but the degree of schistocytosis bears no necessary correlation with other facets of the disorder. More subtle evidence of intravascular hemolysis often is found, such as increased serum levels of lactic acid dehydrogenase and diminished haptoglobin levels. Rarely, massive intravascular hemolysis with hemoglobinemia and hemoglobinuria is noted.¹⁴⁴

Thrombocytopenia is an early and consistent sign of acute DIC, and the consideration of this diagnosis in the presence of a persistently normal platelet count is difficult. Platelet counts in the range of 50,000 to 100,000/µl are the usual finding, but thrombocytopenia may be severe.

Coagulation Defect

The PTT, PT, and thrombin time are prolonged in most patients with acute DIC. Early in the course of the disorder and in chronic DIC, the PTT may be normal or even shorter than normal, which may be the result of the procoagulant effects of activated coagulation factors or elevated factor VIII levels.

Occasionally, one can follow the process of DIC from its inception, and specific assays for various coagulation factors obtained at the time of diagnosis reveal a variable and rapidly changing picture. The plasma levels of fibrinogen and of factors V and XIII usually are significantly depressed; fibrinogen and factor V are the most consistently affected.¹⁶⁷ The level of factor X may be lower than that of other “stable” factors (factors VII, IX, and XI), which usually are present in normal amounts.¹⁶⁷ In many patients, particularly those with abruptio placentae, normal prothrombin levels are maintained,⁹⁹, ¹⁶⁷ but marked hypoprothrombinemia often is present in those with septic DIC.¹⁶⁸

The levels of factors VIII, IX, and XI as determined by onestage assays may fluctuate widely as the result of the presence of activated factors¹⁶⁹ such as thrombin and factor Xa.¹⁶² This problem is minimized in two-stage assays.¹⁶⁷ Levels of factor VIIIc often are normal or increased, particularly when assayed by twostage techniques.¹⁷⁰ In many patients, the levels of coagulation factors tend to “overshoot” after repletion. As a consequence of the inhibitory effects of FDPs, the thrombin time may be prolonged out of proportion to the reduction in the fibrinogen level.

Tests for Fibrinolysis: Fibrin Monomers, Fibrin(ogen) Degradation Products, and D-Dimer

In most patients with DIC, FDP levels as determined by quantitative methods, such as red cell hemagglutination inhibition or latex agglutination, are 25-µg fibrinogen “equivalents”/ml or higher.¹⁶⁷ All methods are most sensitive to large or “early” FDPs. These fragments, particularly fragment X, retain thrombin-binding sites or may form a complex with fibrinogen and consequently be removed during the preparation of serum for FDP tests. This phenomenon or the presence of only small FDPs may explain the normal levels of FDPs in some patients with otherwise typical DIC. Fibrinopeptide A and certain fibrinogen fragments that are formed by the lysis of cross-linked fibrin, such as the DD-dimer and the DD-dimer-E complex, can be demonstrated by using special techniques. These latter FDPs provide direct evidence of the action of thrombin on fibrinogen and provide a means of differentiating fibrin degradation products from fibrinogen degradation products.¹⁷¹, ¹⁷²

The simplicity, specificity, and sensitivity of the D-dimer test have led many laboratories to replace less sensitive or less convenient tests for DIC with the D-dimer test. Because false-positive results may be seen with FDP latex agglutination tests in patients with dysfibrinogenemia, the D-dimer test may be more specific in diagnosing DIC, especially in distinguishing the coagulopathy of liver disease from DIC.⁶⁵, ¹⁶³, ¹⁷³ False-positive D-dimer latex agglutination tests may occur in patients with elevated levels of immunoglobulin M (IgM) (rheumatoid factor).

“Paracoagulation” techniques are simple to perform, but they are less specific than tests for FDPs. The results of the ethanol gelation test, in particular, often are negative in DIC. To the contrary, results of protamine gelation tests usually are positive,¹⁷⁴ but abnormal results are obtained in numerous other disorders, including many that commonly are associated with DIC.

Other Laboratory Findings

Plasma levels of fibrinopeptide A¹⁷⁵ and the rate of incorporation of ¹⁴C-labeled glycine ethyl ester into soluble “circulating fibrin”¹⁷⁶ are exceptionally sensitive indicators of DIC and may be abnormal even in patients with normal levels of FDP. Levels of antithrombin,¹⁷⁷ α₂-antiplasmin, and proteins C and S may be diminished in some cases.

Other parameters of activation of coagulation and fibrinolysis have been studied in DIC, especially in sepsis. Thrombin-antithrombin III (TAT) complexes and plasmin-α₂-antiplasmin (PAP) complexes are often elevated in sepsis-associated DIC. Assays such as TAT and PAP complexes may have prognostic significance in DIC, as may other coagulation parameters, including plasminogen activator inhibitor type-1, vWF antigen, and α₂-antiplasmin.¹⁷⁸ In a primate model of Gram-negative sepsis, a number of molecular markers of coagulation were investigated for their use in monitoring DIC.¹⁷⁹ Markers such as soluble thrombomodulin and soluble fibrin monomer are useful in assessing the status of microvascular injury.

The clinical role of these assays in diagnosing or managing DIC patients at this time is uncertain. The best test for diagnosis and monitoring DIC appears to be a sensitive D-dimer assay; the PTT waveform analysis may also prove to be a useful test. The International Society on Thrombosis and Haemostasis (ISTH) has proposed clinical and laboratory criteria to better define the spectrum of DIC cases.⁹⁰, ¹⁸⁰

Differential Diagnosis

The syndrome of DIC is seldom difficult to recognize. Problems arise when the diagnosis simply is not considered or in chronic forms, when the underlying coagulation disorder may be masked by features of the basic disease or by thromboembolic complications.¹⁸¹

Two disorders, however, produce laboratory abnormalities that resemble DIC: Severe liver disease, which is common, and primary fibrinogenolysis or “pathologic” fibrinolysis, which is rare (Table 54.2).

In patients with primary fibrinogenolysis, the following conditions may be evident: Hypofibrinogenemia; increased levels
of FDP; abnormalities of the PTT, PT, and thrombin time; and deficiencies of factors V and VIIIc. The euglobulin lysis time is significantly and persistently shortened, often in association with plasminemia. However, the platelet count usually is normal, the D-dimer level should be normal or only minimally elevated, and protamine sulfate tests should be negative. Hypoprothrombinemia and deficiencies of stable coagulation factors VII, IX, X, and XI are rare. Thus, routine coagulation tests should be able to distinguish DIC from primary fibrinogenolysis.

In patients with liver disease, coagulation abnormalities and thrombocytopenia may originate from many pathologic processes (Table 54.3). Chronic or intermittent fibrinogenolysis with high levels of FDP is common, particularly in patients with cirrhosis. In such patients, the exclusion of the diagnosis of DIC may be difficult. Factor VIIIc levels usually are elevated when liver disease is severe, and the levels of factors VII and IX typically are low. A helpful test in discriminating between the coagulopathy of liver disease and DIC is the D-dimer test, the results of which should be abnormal in DIC but normal in liver disease (unless additional disorders coexist⁶⁵, ¹⁷³).

DIC, particularly that associated with carcinoma, may be confused with various microangiopathic hemolytic anemias, such as thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome; in these disorders, the clinical picture may resemble that of DIC in many respects. High levels of FDP may be encountered in patients with microangiopathic hemolytic anemias, but significant coagulation abnormalities are not commonly present. Many other disorders may produce slight to moderate elevations of FDP: For example, pulmonary embolism and chronic renal disease with uremia.

Moderate thrombocytopenia is a common consequence of the use of extracorporeal circulatory devices, and coagulation abnormalities often are noted immediately after their use because of the presence of residual heparin. Heparin levels also may rise several hours later (the rebound phenomenon). In such patients, the presence of thrombocytopenia together with the effects of heparin may be confused with DIC; similar difficulties may arise after hemodialysis. Even the small amounts of heparin required to irrigate indwelling catheters, or to contaminate Hickman catheters, are a common cause of “pseudo-DIC.”

Treatment

DIC always is the end result of a serious underlying disorder. Although the patient may benefit greatly from the replacement of depleted coagulation factors and platelets, correction of the syndrome depends on prompt and energetic treatment of the primary disorder. This—not the therapeutic measures described in this section—remains the cornerstone of therapy.

Anticoagulants

Heparin is a specific activator of the physiologic antithrombin system and thereby inhibits a number of proteolytic enzymes, including factors IXa and Xa and thrombin (see Chapter 55). The therapeutic efficacy of heparin is unquestionable in some animal models of DIC, but assessment of its effectiveness in humans has proved more difficult. In view of the complexity of DIC, inhibition of coagulation alters only one facet, albeit a fundamental one, of the pathophysiologic cycle. Recent appreciation of the role of anticoagulation and inflammatory pathways has led to consideration of novel therapies, including replacement of anticoagulant proteins such as antithrombin and APC.¹⁴²

In patients with chronic DIC, the results of heparin therapy usually are favorable and may be dramatic. In most patients, heparin would not be expected to alter ultimate mortality because of the nature of the underlying diseases; however, this drug typically does reduce the severity of bleeding and thromboembolic manifestations and produces parallel improvement in the abnormalities of laboratory test values. Elevated levels of D-dimer and FDPs drop rapidly, and accelerated fibrinolysis, if present, disappears after the administration of heparin, often before the coagulation defect has been alleviated. The response of the platelet count to heparin therapy for DIC is slow and often erratic.

In patients with acute DIC, particularly that associated with sepsis, the results of heparin therapy have been less encouraging.¹⁸² Most clinicians are reluctant to use heparin in patients with acute DIC. Because baseline PTT values are usually prolonged in acute DIC, heparin levels may be required to monitor therapy (see Chapter 55).

Replacement Therapy with Platelets and Coagulation Factors

Many patients with DIC ultimately receive large amounts of blood products, even though evidence is only anecdotal that they are necessary or therapeutically effective.¹⁸³ The major aim of replacement therapy with blood products in DIC is to replenish fibrinogen. This goal is best accomplished by the administration of cryoprecipitate, each unit of which contains approximately 250 mg of fibrinogen.¹⁸⁴ The amount of cryoprecipitate given should be sufficient to elevate the plasma fibrinogen level to at least 100 to 150 mg/dl. As a general guide, 3 g of fibrinogen can be expected to raise the plasma level of an adult patient approximately 100 mg/dl. Fibrinogen administration probably should be restricted to the occasional patient with hypofibrinogenemia and significant bleeding, in whom DIC is self-limited or has been controlled by heparin therapy (e.g., in intrauterine fetal death before surgical intervention). Sterile fibrinogen concentrates are not yet available for routine therapeutic use in the United States.

Patients with DIC, bleeding, and platelet counts <50,000/µl should be considered for platelet transfusion. Due to the acquired storage pool defect seen with DIC, as well as FDP inhibition of platelet function, DIC patients may require a higher platelet count for adequate hemostasis than patients with thrombocytopenia in the absence of platelet dysfunction.

The availability of purified, sterile antithrombin concentrates has led to its investigation in treating DIC. As seen in most studies,¹⁸⁵ although antithrombin concentrates can normalize plasma levels of this protein in patients with DIC and improve hemostasis parameters, consistent clinical benefit in terms of survival is not evident. A large clinical trial demonstrated that high-dose antithrombin therapy in patients with sepsis had no effect on mortality.¹⁸⁶ A post hoc analysis of this clinical trial indicated that high-dose antithrombin therapy may be effective in improving survival in the subset of patients with severe sepsis and high risk of death, especially if concomitant heparin treatment is avoided.¹⁸⁷ Prospective studies will be important to confirm this subgroup analysis.

Other Therapeutic Measures

Treatment of shock should be immediate and vigorous in all patients with DIC. Packed erythrocytes should be given promptly if indicated. The indiscriminate use of ε-aminocaproic acid (EACA) and other antifibrinolytic drugs should be discouraged. Because of the potential risks, fibrinolytic enzyme inhibitors should be administered only to carefully selected patients, that is, those in whom DIC has resulted from a transitory stimulus or has been arrested by heparin administration and in whom fibrinogenolysis or inappropriate fibrinolysis, hypofibrinogenemia, and adequate renal function have been clearly documented. The therapeutic use of EACA in fibrinogenolysis and appropriate dosage schedules are discussed elsewhere in this chapter.

Specific Features of Various Forms of Disseminated Intravascular Coagulation

Obstetric Disorders

Abruptio Placentae

DIC complicates abruptio placentae in approximately 10% of cases¹⁸⁸ in which fetal compromise occurs. Shock develops rapidly, but vaginal bleeding may be minimal or absent for a time and bears little relationship to the extent of abruption. Brisk external hemorrhage may originate from episiotomies and lacerations, and large amounts of blood may be concealed behind the placenta and within the wall of the uterus. Severe placental abruption associated with fetal death is often linked with DIC.¹⁸⁹

Hemorrhage is the major factor leading to shock and renal complications in abruptio placentae, and the most essential therapeutic measures are the vigorous treatment of blood loss and the prompt evacuation of the uterus. Extensive replacement therapy seldom is required. Often, fibrinogen replacement is given if immediate surgical treatment is necessary. Fibrinogen replacement may be most useful in patients with fetal death requiring cesarean delivery. If the coagulation defect and thrombocytopenia are severe or persist for an unusually long time, the administration of platelets, fibrinogen in the form of cryoprecipitate, and fresh frozen plasma¹⁹⁰ may reduce hemorrhage. Most obstetricians do not administer heparin because it may increase bleeding and because rapid spontaneous remission of DIC is usual when the uterus is evacuated.

Intrauterine Fetal Death

In the event of intrauterine fetal death, definite laboratory abnormalities are not seen until the dead fetus has been retained for ≥5 weeks¹⁸⁸; plasma levels of FDPs then begin to rise, and the platelet count and fibrinogen level gradually decline. Bleeding may be inconspicuous, but a progressive loss of renal function is not uncommon. In most women in whom delivery of the dead fetus is induced promptly according to usual obstetric practice, bleeding is not serious, even in the presence of low-grade DIC. Operative intervention is dangerous when hypofibrinogenemia is severe, and such patients should receive heparin until safe fibrinogen levels are restored.¹⁹¹ If immediate surgery is imperative, heparin administration should be followed by platelet replacement and enough fibrinogen, in the form of cryoprecipitate, to produce plasma fibrinogen levels of 150 mg/dl or greater.¹⁹²

Amniotic Fluid Embolism

In women who survive amniotic fluid embolism (mortality rate of up to 80% in early studies), DIC with severe hemorrhage may develop within 1 to 2 hours.¹⁶², ¹⁹³ More recent surveys indicate a mortality rate of 20% to 30%¹⁹⁴; 50% of patients with amniotic fluid embolism had DIC.¹⁸⁸ Often, the syndrome is complicated by significant fibrinolysis and even fibrinogenolysis.¹⁴⁸ Hypoxia and other sequelae of pulmonary vascular obstruction dominate the clinical picture and usually determine the outcome. The release of serotonin and other vasoactive substances from platelets may contribute to the profound pulmonary vasoconstriction.

Miscellaneous Obstetric Disorders

Intravascular coagulation has been documented after abortions induced by intra-amniotic injection of hypertonic saline solutions¹⁹⁴ and hypertonic urea,¹⁹⁵ but it apparently does not complicate abortions performed by suction curettage or those induced by prostaglandin F₂α.

Disseminated Intravascular Coagulation in Neonates and Infants

Several disorders unique to the neonate and infant may be associated with DIC (Table 54.2).¹⁹⁶ The transplacental passage of thromboplastins or other procoagulant substances has been the apparent cause of DIC in neonates born of mothers affected with DIC owing to abruptio placentae, eclampsia, or septicemia. Asphyxia may be a common precipitating factor for DIC in these disorders.¹⁹⁷ Bacterial infection and generalized viral infections (e.g., herpes simplex, cytomegalic inclusion disease, and rubella), acidosis, and hypoxia are more common causes of DIC in infants than in adults.¹⁹⁸ DIC secondary to giant hemangiomas and purpura fulminans has been reported in neonates.

Management of septic DIC in the neonate should emphasize treatment of underlying infection. A controlled study that compared treatment with heparin, extensive replacement therapy with blood products, and supportive care only revealed no significant differences in outcome for the three groups.¹⁹⁹ A more recent study confirms that clinical trials in neonatal sepsis have not identified a beneficial therapy.²⁰⁰

The diagnosis seldom is difficult, but DIC must be distinguished from septic shock, endotoxin shock, or simple thrombocytopenia, all of which may develop independently of DIC in severe infections.²⁰¹

In many patients, no additional measures other than treating infection and shock (if present) are required. No evidence has been cited that heparin has diminished mortality.¹⁶⁸ In one series, the alleviation of septic shock appeared to be more important in the ultimate prognosis than did correction of the coagulation abnormalities.¹⁶⁸ Recombinant APC (r-APC) was demonstrated in one study to reduce mortality in adult patients with sepsis²⁰²; however, a Cochrane database review of the effects of r-APC in neonates with sepsis concluded that there were insufficient data to support the use of the drug in the pediatric setting.²⁰³ Subsequent studies in adult patients demonstrating no clinical benefit of r-APC in sepsis led to withdrawal of this drug.

Purpura Fulminans

The hemorrhagic manifestations of purpura fulminans develop several days after an acute infection; these are most commonly scarlet fever or various viral respiratory diseases. Purpura fulminans is most common in children but is also well documented in adults. The most common manifestations are symmetric ecchymoses of the lower extremities and buttocks, sharply circumscribed infarcts of the skin and genitalia, and gangrene of the extremities that often involves the digits symmetrically.²⁰⁴ These ecchymotic lesions often become necrotic, ultimately forming blood-filled bullae (Fig. 54.4). Petechiae are rare. Fever and prostration are seen, but visceral lesions, including renal involvement, are relatively uncommon.

The mortality rate associated with purpura fulminans ranges from 18%²⁰⁵ to 40% to 70%.²⁰⁶ Heparin in therapeutic doses has often proved therapeutically effective, and it has been suggested that poor results obtained previously with this anticoagulant reflect late treatment of moribund patients. In patients with purpura fulminans, relapses are particularly common after cessation of heparin therapy,²⁰⁵ and the administration of this anticoagulant, possibly in reduced doses, should always be continued for 2 to 3 weeks. The subject of purpura fulminans diagnosis and treatment has been recently reviewed.²⁰⁷ Evidence that purpura fulminans may be a manifestation of homozygous protein C deficiency is discussed in Chapter 55. The efficacy of protein C in patients with sepsis and purpura fulminans is discussed below.

Neoplastic Disorders

Carcinoma

In patients with DIC associated with carcinoma, the clinical picture is quite variable and often consists of a combination of bleeding and thromboembolic phenomena, including arterial embolism.⁹⁸, ¹⁰², ¹⁰³ The association of chronic DIC,
thromboembolism, and cancer is often called Trousseau syndrome.⁹⁸ Laboratory findings are variable. Evidence of chronic DIC, hypercoagulability, or acute DIC may be found. In a study of more than 1,000 patients with solid tumors, 7% were diagnosed with DIC using standard coagulation tests (platelet count, fibrinogen, D-dimer, FDPs).²⁰⁸ Risk factors associated with the occurrence of DIC included older age, male gender, advanced disease, breast cancer, and necrosis of the tumor specimen.²⁰⁸

One reason for the variability in cancer patients having venous thromboembolism relates to the histology of the malignancy. Analysis of a very large database of Medicare patients with cancer identified tissue-specific differences in thrombotic risks among cancers.²⁰⁹ Those cancers with a high risk of thrombosis included uterine, brain, leukemia, ovary, and pancreas (twofold or greater risk), whereas prostate, liver, head or neck, bladder, and breast cancer had less than a onefold risk (compared to noncancer patients).²⁰⁹

DIC in association with carcinoma resolves with effective treatment of the underlying tumor. Heparin or low-molecular-weight heparin (LMWH) in therapeutic doses has proved effective in controlling the hemorrhagic and thromboembolic symptoms.⁹⁸, ¹⁰², ²¹⁰ There is a suggestion in the literature that the use of LMWH therapy is associated with improved mortality in cancer patients. A large European study of patients with noncurable solid tumors evaluated the survival effects of a LMWH (nadroparin) given in therapeutic dose for 2 weeks followed by half-dose for 4 weeks.²¹¹ There was significant improvement in survival in the LMWH group with minimal toxicity.²¹¹ The basis for this antitumor activity of LMWH may not relate to anticoagulant activity.²¹² A recent Cochrane literature review of the effects of anticoagulation on cancer patient survival found improved survival after 24 months, but not 12 months.²¹³

A significant minority of patients with cancer and thrombosis will experience recurrent thrombosis with oral anticoagulation⁹⁸ and will benefit from long-term heparin or LMWH.²¹⁴ Based on these data, optimal anticoagulant therapy for cancer patients with thrombosis is LMWH. In the case of DIC associated with prostate cancer, adjunctive therapy with ketoconazole²¹⁵ or antiandrogens²¹⁶ may be useful.

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