CHAPTER 16: Acquired Coagulation Disorders

One of the most challenging aspects of clinical medicine is the diagnosis and treatment of acquired bleeding disorders. These problems commonly arise in hospitalized patients on medical, surgical, and obstetrical services. The immediate question of whether the bleeding is due to recent trauma or surgery is sometimes difficult to answer with certainty. A careful history may reveal an inherited bleeding disorder or exposure to drugs or toxins that might adversely affect platelet or coagulation functions. A thorough physical examination will usually reveal whether the bleeding is local and restricted to the area of trauma or surgery, rather than widespread. In any case, a patient with unexplained hemorrhage, local or systemic, should be initially evaluated and then closely monitored with baseline screening tests that include a platelet count, prothrombin time, and partial thromboplastin time. Occasionally, additional coagulation tests are needed to delineate the cause of the bleeding and to guide appropriate therapy. Skillful management of these patients, who often have complex illnesses, must be based on a solid understanding of the pathophysiology of hemostasis, as presented in Chapter 13 and amplified in this chapter.

In contrast to inherited conditions such as hemophilia (Chapter 15), acquired bleeding disorders usually involve deficiencies of multiple clotting factors. This chapter will focus primarily on three problems commonly encountered on medical and surgical floors: vitamin K deficiency, severe liver disease, and disseminated intravascular coagulation (DIC).

Vitamin K is a fat-soluble organic compound found primarily in leafy green vegetables but also in meat and dairy products. It is composed of a bicyclical naphthoquinone backbone and an aliphatic side chain. As shown in Figure 16-1, vitamin K is converted to the hydroquinone by a vitamin K reductase. The hydroquinone is an essential cofactor utilized by the vitamin K–dependent carboxylase to catalyze the oxidative fixation of carbon dioxide onto specific glutamic acid residues to form γ-carboxyglutamic acid. During this reaction vitamin K is converted to an epoxide, which is then converted back to the quinone by a vitamin K epoxide reductase. This vitamin K–dependent post-translational modification takes place in the Golgi apparatus of many cell types and is restricted to specific domains on a small number of proteins—those known as vitamin K–dependent proteins. In hepatocytes, γ-carboxylation is necessary for the biologic activity of the vitamin K– dependent coagulation factors: the zymogens prothrombin, factors VII, IX, and X (Fig. 16-2), as well as protein C and protein S. In bone, γ-carboxylation is necessary for the synthesis of osteocalcin and matrix Gla protein. In all cases, this structural modification enables binding of divalent calcium. The function of vitamin K– dependent clotting factors requires calcium binding in order to form procoagulant complexes on membrane surfaces.

Vitamin K is absorbed in the intestine. Sources of vitamin K include food and vitamin K synthesized by flora in the gut. Accordingly, patients who are not eating and who are receiving broad-spectrum antibiotics are at risk for becoming vitamin K deficient. This scenario is commonly encountered, particularly in hospitalized patients, and is often not diagnosed until they develop clinically significant bleeding. Less often, vitamin K deficiency is caused by obstructive liver disease or by disorders of the intestinal mucosa that lead to chronic malabsorption.

Formerly, vitamin K deficiency in newborns sometimes caused ecchymoses, bleeding from venipuncture sites, and, rarely, intracranial hemorrhage. Hemorrhagic disease of the newborn arises because plasma levels of vitamin K–dependent clotting factors are relatively low at birth, the gastrointestinal tract of the newborn is relatively sterile, and mother's milk contains very little vitamin K. The risk is enhanced if the mother has been taking antibiotics or anticonvulsant drugs. Fortunately, this complication is now rarely encountered, owing to the routine administration of vitamin K to newborns.

An important and common cause of functional "vitamin K deficiency" is overdosage with anticoagulant drugs, primarily warfarin. These drugs are competitive inhibitors of vitamin K epoxide reductase (Fig. 16-1). As shown in Figure 16-3, warfarin administration results in a decrease in γ-carboxylation of prothrombin and other vitamin K–dependent clotting factors. Patients taking warfarin are carefully monitored through regular measurement of the prothrombin time, which allows the dose of warfarin to be adjusted to maintain the patient within a safe and effective anticoagulant range. Patients are at risk of abnormal bleeding when the prothrombin time significantly exceeds this range. Occasionally, mentally disturbed patients develop hemorrhage after self-administration of toxic doses of warfarin or another vitamin K antagonist such as rodent poison.

DIAGNOSIS

In patients with vitamin K deficiency, the prothrombin time is prolonged, often markedly so, owing to functional impairment of prothrombin, factor VII, and factor X. The partial thromboplastin time is also prolonged but to a lesser extent, due to the impairment of prothrombin, factor IX, and factor X. In patients in whom vitamin K deficiency is not apparent from the history or clinical setting, functional assays of specific clotting factors will reveal low levels of prothrombin and factors VII, IX, and X. In contrast, immunologically based assays would demonstrate that the protein levels of these factors are normal or near normal, thereby providing strong evidence for a change in structure that impairs function.

TREATMENT

In many patients, vitamin K deficiency is anticipated and diagnosed prior to any apparent abnormal bleeding. These individuals and those with mild abnormal bleeding can be treated with parenteral administration of vitamin K. The prothrombin time should reach normal levels within about 12 hours of initiating therapy. Patients with severe bleeding should receive not only vitamin K but also infusion of fresh frozen plasma or plasma concentrates that are enriched in prothrombin and factors VII, IX, and X. Concern for the transmission of viral diseases lessens the use of prothrombin concentrates unless they have been prepared free of contaminating viruses.

The hepatocyte is the only site of synthesis of the vitamin K–dependent coagulation proteins and is the primary, though not the only, site at which factor VIII is produced. Therefore patients with severe liver disease may develop abnormal bleeding due to low levels of these clotting proteins. Moreover, most of these patients develop functionally abnormal fibrinogen due to enhanced glycosylation. The prothrombin time and the partial thromboplastin time are prolonged, and if dysfibrinogenemia is present, the thrombin time is also prolonged.

In patients with liver disease, the risk of abnormal bleeding due to defects in coagulation is often compounded by thrombocytopenia caused either by congestive splenomegaly in patients with cirrhosis or suppression of platelet production in patients with alcoholism. Moreover, patients with impaired liver function fail to clear activated clotting factors from the circulation and therefore are predisposed to developing DIC, discussed in the next section.

In patients with liver disease, abnormal bleeding is primarily from the gastrointestinal tract, due to a combination of low levels of plasma coagulation proteins, thrombocytopenia, and anatomical lesions secondary to the underlying liver disease and its cause. For example, patients with cirrhosis may have esophageal varices, whereas patients with alcoholism often have not only hepatic cirrhosis but also alcohol-induced gastric erosions. Thus, gastrointestinal bleeding is a common problem in patients with liver disease, owing to a complex array of comorbid conditions.

In those patients who are actively bleeding, attention must be directed both to local sites of blood loss as well as correction or amelioration of abnormal hemostasis.

Vitamin K should be administered because many of these patients are vitamin K deficient, particularly if they have obstructive liver disease. In most patients, thrombocytopenia can be partially corrected by infusion of platelets. Correction of deficits in plasma coagulation proteins is more challenging, particularly in patients with DIC.

The most formidable and daunting disorder of hemostasis is DIC. This life-threatening complication is commonly encountered in a variety of medical, surgical, and obstetric settings. The pathophysiology of DIC is complex, but at its core is the release of tissue factor or the exposure of blood to endotoxin in sufficient amounts to activate blood coagulation and overwhelm normal hemostatic regulatory mechanisms. As a result, the coagulation cascade is ignited to such a degree that coagulation factors are consumed along with platelets. This process is accompanied by secondary fibrinolysis due to activation of plasmin, which may digest any fibrin that is formed. Depending on the balance of pro-thrombotic and anti-thrombotic derangements, pathology sections may show widespread deposition of fibrin and platelets throughout the microcirculation accompanied by tissue damage, hemorrhage, or a combination of both.

ETIOLOGY AND PATHOGENESIS

DIC never arises de novo but rather as a consequence of an underlying pathologic process. Further insight into the pathogenesis of DIC can be gained by a consideration of the myriad of disorders that are known triggers, the most important of which are shown in Table 16-1.

In many of these conditions, the release of tissue factor from injured vessels or extravascular cells plays a central role in unleashing the full potential of the blood coagulation pathway (Fig. 16-4). In addition, injury to the endothelium can cause in situ thrombus formation due to both adhesion of platelets and down-regulation of thrombomodulin, which normally converts circulating thrombin into an anticoagulant (Chapter 17). Sepsis is the most common trigger of DIC among medical or surgical in-patients. The production of endotoxin by the offending organism activates monocytes, provoking the release of both endogenous tissue factor and inflammatory cytokines such as tumor necrosis factor and interleukin-1, which in turn induce robust expression of tissue factor. DIC also may be initiated by diffuse vascular injury caused by hypoxia, acidosis, and shock, often coexisting in very sick patients, as well as by antigen–antibody complexes, such as are present in systemic lupus erythematosus.

Intravascular coagulation can also be triggered by release of tissue factor from pathologic tissue. DIC occurs in obstetrical patients as a result of a number of complications listed in Table 16-1. In many of these patients, DIC is induced by the release of fetal cells or fluid into the maternal circulation. Obstetrical DIC usually resolves promptly with surgical correction of the problem. In addition, procoagulant material can be released in certain malignant conditions. In acute promyelocytic leukemia (Chapter 21), the turnover of granule-laden leukemic cells releases procoagulants that often lead to severe DIC. Patients with certain solid tumors, particularly mucus-producing adenocarcinomas, sometimes have a more chronic and indolent form of DIC.

Clinical presentation and manifestations are variable, as shown in Figure 16-5. Patients with severe acute DIC commonly have diffuse bleeding, most often ecchymoses in skin and mucous membranes as a result of thrombocytopenia, but occasionally more serious and extensive blood loss. Some patients have profuse gastrointestinal bleeding, usually from multiple sources. Others develop pulmonary or uterine bleeding, hematuria, wound hemorrhage, or spontaneous bleeding from venipuncture sites. The more serious bleeding is due to a combination of thrombocytopenia, deficiency of coagulation factors, and secondary fibrinolysis. A much smaller subset of patients presents with thrombosis, often localized to the fingertips and toes, but sometimes causing necrosis of internal organs such as the renal cortex or bowel. Critically ill patients with the underlying conditions listed in Table 16-1 often have no clinically apparent bleeding or thrombosis but yet have the laboratory abnormalities of DIC. Obviously, these patients require close surveillance.

LABORATORY DIAGNOSIS

Patients with DIC have both thrombocytopenia and global abnormalities in the coagulation profile, as shown in the sidebar. Examination of the peripheral blood smear not only confirms the thrombocytopenia but also reveals relatively large platelets, indicative of enhanced platelet consumption rather than impaired production. In addition, in about one-quarter of patients with DIC, the red cell morphology is abnormal, with fragmented, triangular, and helmet-shaped cells, shown in Figure 16-6B, identical to the morphology encountered in microangiopathic hemolytic disorders such as thrombotic thrombocytopenic purpura (Chapter 14). However, patients with DIC have much less hemolysis than those with thrombotic thrombocytopenic purpura. Abnormal red cell morphology in DIC is due to shear stress as red cells are catapulted through a meshwork of fibrin strands. The markedly abnormal coagulation profile is due in part to low levels of clotting factors, owing to ongoing consumption. In addition, fibrin degradation products generated by ongoing fibrinolysis are potent inhibitors of thrombin.

TREATMENT

The cardinal mandate in the management of DIC is to first treat the underlying disease. The patient's bleeding, thrombosis, and accompanying laboratory abnormalities may be promptly and fully reversed by effective therapy of the underlying condition—that is, antibiotic treatment of sepsis, surgical debridement of trauma wounds, and removal of fetal and placental tissue from the uterus. Unfortunately, in many (and perhaps most) cases of DIC, it is not possible to effectively treat the underlying disease. In these patients, active bleeding can be controlled by the administration of platelets, fresh frozen plasma, and sometimes coagulation factor concentrates. In patients with thrombosis, careful administration of heparin may be effective. In the absence of either bleeding or thrombosis, close monitoring is crucial because the clinical status of patients with DIC can deteriorate very rapidly.

ACQUIRED INHIBITORS OF COAGULATION FACTORS

Patients may develop profuse and widespread bleeding due to the development of antibodies that specifically inhibit one of the coagulation factors. Factor VIII inhibitors, albeit rare, are encountered more often than those against other coagulation proteins and can cause catastrophic bleeding. This problem may occur de novo but is seen more often postpartum or in patients with lymphoid malignancies or chronic inflammatory disorders. Because the titer of anti-factor VIII antibody is usually very high, the management of these patients is as challenging as that of hemophilia patients who develop a factor VIII inhibito (Chapter 15). Even less often encountered are bleeding disorders due to acquisition of antibody inhibitors of other coagulation proteins such as factor V and von Willebrand factor.

Acquired factor X deficiency is sometimes seen in patients with amyloidosis due to binding and rapid clearance of factor X by amyloid.

ANTIPHOSPHOLIPID SYNDROME

Individuals who develop antiphospholipid antibodies often have a slightly prolonged prothrombin time and a significantly prolonged partial thromboplastin time but are at risk of thrombosis rather than bleeding. This entity is discussed in Chapter 17.