Acquired Coagulation Disorders

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.


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.

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


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).

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.


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.


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)


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)


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


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

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.)

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


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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Oct 21, 2016 | Posted by in HEMATOLOGY | Comments Off on Acquired Coagulation Disorders
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