Coagulation Disorders Part 2

Factor XI Deficiency

Patients with factor XI deficiency frequently come to medical attention when a prolonged aPTT is detected in preoperative screening. It is most frequently observed in Ashkenazi Jews, although sporadic cases have been described in people of different ethnic origins. Factor XI deficiency is inherited as an autosomal recessive trait, and heterozygous deficiency is not associated with any clinical bleeding. Homozygous or compound heterozygous deficient patients generally have factor XI levels of less than 15%, and most bleeding manifestations in these patients are related to trauma or surgery, especially at sites of high fibrinolytic activity (e.g., the urinary tract, tonsils, and tooth sockets).28 Factor XI plays a supportive role in the clotting cascade. It is activated by thrombin and then functions in a positive feedback manner to augment thrombin generation and clot stabilization [see 5:XIIHemostasis and Its Regulation]. Thus, factor XI is primarily required in situations in which there is a significant he-mostatic challenge; this explains the mild bleeding diathesis in factor XI deficiency.

For patients with severe factor XI deficiency (< 15%) who require surgery, fresh frozen plasma should be used to replenish the plasma level to more than 50%. EACA given orally at a dosage of 3 g three or four times daily is also effective for minor surgical or dental procedures. In a recent retrospective study of 62 women with severe factor XI deficiency, about 70% of the women did not have any postpartum hemorrhage. Of the 30% who did have postpartum hemorrhage, some had a history of recurrent clinical bleeding. Postpartum hemorrhage had no relationship with the particular abnormal factor XI genotype or with the level of factor XI.29

Fibrinolytic Abnormalities

Two uncommon congenital hemorrhagic disorders have been ascribed to abnormalities of fibrinolysis. Deficiency of a2-anti-plasmin, the major plasmin inhibitor, has led to uncontrolled plasmin activity with consequent hemorrhage. Enhanced fibri-nolytic activity with occasional clinical bleeding has also been linked to deficiency of plasminogen activator inhibitor-1 (PAI-1), the physiologic inhibitor of tissue plasminogen activator (t-PA) and urokinase.30 Treatment of both types of fibrinolytic abnormalities consists of the antifibrinolytic agents, tranexamic acid, or EACA, all of which block the binding of plasminogen and plasmin to fibrin.

Acquired Hemorrhagic Disorders

In addition to the hereditary coagulation disorders, several acquired disorders have been identified that can lead to generalized hemorrhage.

Vitamin K Deficiency

A vitamin K-dependent carboxylase in the liver synthesizes y-carboxyglutamic acid, which is required for the biologic function of prothrombin and factors VII, IX, and X. In the absence of vitamin K, an abnormal prothrombin that lacks y-carboxyglutamic residues is synthesized. Specific immunoassays performed in patients with vitamin K deficiency reveal a sharp decrease in normal prothrombin levels and a concomitant increased level of the abnormal des-y-carboxyprothrombin. The same molecular derangement occurs with factors VII, IX, and X.31

Clinical Features and Diagnosis

Deficiency of vitamin K, which decreases levels of prothrombin and factors VII, IX, and X, occurs in cases of severe malnutrition, intestinal malabsorption, and obstructive jaundice. In patients with obstructive jaundice, bile salts, which are necessary for the emulsification and absorption of the fat-soluble vitamins (vitamins A, D, E, and K), cannot enter the intestine. Long-term ingestion of oral antibiotics suppresses vitamin K production by intestinal organisms. The effect is especially marked in patients who, because of their illness, are unable to consume a full, nourishing diet. Mucosal bleeding and ecchymoses occur if the pro-coagulant levels fall below 10% to 15% of normal.


Therapy with vitamin K1 (phytonadione), 10 to 25 mg/day orally for 2 or 3 days—or parenteral vitamin K1 in cases of obstructive jaundice—usually reverses the abnormality in about 6 to 24 hours. If there is severe bleeding, fresh frozen plasma (approximately 3 units) restores procoagulant levels rapidly [see Principles of Replacement Therapy, above].

Drug-Induced Hemorrhage

Warfarin-Induced Hemorrhage

Warfarin overdose or potentiation of its action by other drugs can cause very severe bleeding. The prothrombin time (PT) is prolonged, and mucosal bleeding, gastrointestinal bleeding, or ecchymosis is the usual pattern. If hemorrhage is significant, treatment to restore procoagulant levels to 30% of normal must be started with fresh frozen plasma. If there is no urgency, oral vitamin K1 may be given. Generally, 1 to 2.5 mg of vitamin K1 will be sufficient to return anticoagulation (defined as the international normalized ratio [INR]) to therapeutic levels after 16 hours. High doses of vitamin K1 (10 mg or more) should be avoided because they may cause warfarin resistance for up to a week. Surreptitious warfarin use can be identified by a serum warfarin assay, which is available at special laboratories. Factitious or accidental ingestion of some of the long-acting vitamin K antagonists that are used as rodenticides (superwarfarins) may lead to prolonged bleeding symptoms. The synthesis of vitamin K-dependent clotting factors can be impaired for months after the initial exposure. Repeated administration of fresh frozen plasma, supplemented by massive doses of oral vitamin K1 (100 to 150 mg/day), may be required to control bleeding symptoms.

Heparin-1nduced Hemorrhage

Heparin overdose may not be obvious. It causes subcutaneous hemorrhages and deep tissue hematomas. The aPTT, PT, and thrombin time (TT) are vastly prolonged, but the reptilase time (RT) is normal. Intravenous protamine administration at a dosage of 1 mg/100 U of administered heparin terminates the overdose response. Because the half-life of protamine is shorter than that of heparin, a heparin rebound may occur, necessitating a second administration of protamine. Low-molecular-weight heparin (LMWH) preparations cause as much bleeding as standard unfractionated heparin. The ability of protamine to reverse the actions of LMWH is incomplete. Protamine (1 mg/100 U of anti-factor Xa) can be tried; if protamine treatment is unsuccessful, recombinant factor VIIa should be considered.

Hemorrhage Caused by Thrombolytic Therapy

Thrombolytic therapy is now used for acute myocardial infarction and for some cases of pulmonary embolism. The complications of thrombolytic therapy are essentially all hemorrhagic. In general, bleeding has been confined to relatively trivial oozing at vascular invasion sites, but subdural hematomas, cerebral infarction, and intracranial bleeding have also occurred. The thrombolytic agents, even those designed to be relatively fibrin specific, occasionally cause a significant systemic lytic state, with low levels of fibrinogen, factor V, and factor VIII. Furthermore, the generation of fibrinogen degradation products in turn interferes with the formation of a firm clot and with platelet function.

If thrombolytic therapy is suspected as the cause of bleeding in a particular patient, blood should be drawn quickly for an aPTT, a TT, an RT, and a fibrinogen level. If thrombolytic thera-py is the cause, the aPTT is prolonged, the fibrinogen level is usually below 50 mg/dl, and the TT and RT are both prolonged (as a result of the fibrin degradation products and decreased plasma fibrinogen).

Table 3 Causes of Disseminated Intravascular Coagulation (DIC)

Events that initiate DIC


Cancer procoagulants (Trousseau syndrome)

Acute promyelocytic leukemia

Crush injury, complicated surgery

Severe intracranial hemorrhage

Retained conception products, abruptio placentae, amniotic fluid embolism

Eclampsia, preeclampsia

Major ABO blood mismatch, hemolytic transfusion reaction

Burn injuries


Malignant hypertension

Extensive pump-oxygenation (repair of aortic aneurysm)

Giant hemangioma (Kasabach-Merritt syndrome)

Severe vasculitis

Events that complicate and propagate DIC


Complement pathway activation

The disorder is treated with cryoprecipitate (to raise the fibrinogen level to approximately 100 mg/dl), fresh frozen plasma, and platelet concentrates. If these measures do not stop the bleeding, the use of a specific antifibrinolytic agent such as EACA should be considered. EACA is given as a 5 g bolus I.V. over 30 to 60 minutes and then in a dosage of 1 g/hr by continuous I.V. infusion.32


The abnormal proteins associated with myeloma and macro-globulinemia can interfere with platelet function and cause clinical bleeding. These proteins can cause abnormalities in the coagulation tests as well. Both IgG and IgA myeloma proteins can cause prolonged TTs by interfering with the fibrin polymerization process. Less commonly, they may interact with specific clotting factors. Management is directed at the primary disease. Generally, these paraproteins do not cause clinically significant bleeding. If bleeding occurs, plasmapheresis rapidly corrects the defects by abruptly lowering the level of abnormal protein.

Disseminated Intravascular Coagulation


Many different circumstances can cause DIC [see Table 3]. In each case, massive activation of the clotting cascade overwhelms the natural antithrombotic mechanisms, giving rise to uncontrolled thrombin generation. This condition results in thromboses in the arterial and venous beds, leading to ischemic infarction and necrosis that intensify the damage, release tissue factor, and further activate the clotting cascade. Massive coagulation depletes clotting factors and platelets, giving rise to consumption coagulopathy and bleeding. Tissue damage and the deposition of fibrin result in the release and activation of plasminogen activators and the generation of plasmin in amounts that overwhelm its inhibitor, a2-antiplasmin. Plasmin degrades fibrino-gen, prothrombin, and factors V and VIII and produces fibrin-fibrinogen degradation products. These substances interfere with normal fibrin polymerization and impair platelet function by binding to the platelet surface GPIIb-IIIa fibrinogen receptor. These fibrin-fibrinogen degradation products thus function as circulating anticoagulant and antiplatelet agents, exacerbating the consumption coagulopathy, and play a significant role in the bleeding diathesis [see Figure 1 ].

Endotoxin released during gram-negative septicemia enhances the expression of tissue factor, thereby accelerating procoagu-lant activation while suppressing thrombomodulin expression. These actions downregulate the protein C/protein S system, further promoting the tendency to DIC.33 Experimental-endotox-emia models also showed marked suppression of fibrinolysis activity caused by a sustained increase in plasma PAI-1.34 In patients with solitary or multiple hemangiomas associated with thrombocytopenia (Kasabach-Merritt syndrome), DIC is presumably initiated by prolonged contact of abnormal endothelial surface with blood in areas of vascular stasis. Platelets and fibrinogen are consumed in these hemangiomas, where fibrinolysis appears to be enhanced,35 and such consumption can lead to hemorrhage. Certain snakebites can also produce DIC; several mechanisms have been identified. For example, Russell viper venom contains a protease that directly activates factor X and can produce almost instantaneous defibrination.

Clinical Consequences

The consequences of DIC depend on its cause and the rapidity with which the initiating event is propagated. If the activation occurs slowly, an excess of procoagulants is produced, predisposing to thrombosis. At the same time, as long as the liver can compensate for the consumption of clotting factors and the bone marrow maintains an adequate platelet output, the bleeding diathesis will not be clinically apparent.

In compensated disseminated intravascular coagulation (DIC), such as that which occurs in Trousseau syndrome, thrombotic manifestations predominate in the clinical presentation. In decompensated DIC, however, fibrin-fibrinogen degradation products exacerbate the consumption coagulopathy and play a significant role in the bleeding diathesis.

Figure 1 In compensated disseminated intravascular coagulation (DIC), such as that which occurs in Trousseau syndrome, thrombotic manifestations predominate in the clinical presentation. In decompensated DIC, however, fibrin-fibrinogen degradation products exacerbate the consumption coagulopathy and play a significant role in the bleeding diathesis.

The clinical situation consists of primarily thrombotic manifestations, which can be both venous thrombosis and arterial thrombosis [see 5:XIV Thrombotic Disorders]. Venous thromboses commonly involve deep vein thrombosis in the extremities or superficial migratory thrombophlebitis. Patients can also experience arterial thrombosis, leading to digital ischemia, renal infarction, or stroke. Arterial ischemia can in part be the result of emboli that originate from fibrin clots in the mitral valve, a condition termed nonbac-terial thrombotic endocarditis, or marantic endocarditis. This condition is sometimes known as compensated, or chronic, DIC and accounts for Trousseau syndrome36 (a chronic DIC caused by an underlying malignancy, most frequently pancreatic or other gastrointestinal cancer). The cancer cells may produce either tissue factor or another procoagulant that activates the clotting system.

If the reaction is brisk and explosive, the clinical picture is dominated by intravascular coagulation; depletion of platelets, fibrinogen, prothrombin, and factors V and VIII; and the production, by plasmin action, of fibrin degradation products, which further interfere with hemostasis. The clinical consequence is a profound systemic bleeding diathesis, with blood oozing from wound sites, intravenous lines, and catheters, as well as bleeding into deep tissues. The intravascular fibrin strands produce mi-croangiopathic hemolytic anemia.


Microangiopathic red blood cells on smear and a moderate to severe thrombocytopenia suggest the diagnosis. A number of laboratory abnormalities are present in DIC, depending on the stage of the DIC. Because of clotting factor depletion, the aPTT and PT are prolonged and the fibrinogen level is low. Because fibrin degradation products interfere with fibrin polymerization, the TT and RT are also prolonged. The level of fibrin degradation products, as measured by the D-dimer level, is elevated. Plasma plasminogen, protein C, and a2-antiplasmin levels are also low because of consumption; however, these measurements are generally not required. In the case of compensated DIC, most of these parameters can be normal except for the elevation of the D-dimer level, which indicates the presence of intravascular cross-linked fibrin deposition and fibrinolysis. Sometimes, the fibrinogen level can even be high because fibrinogen is an acute-phase reactant. When the DIC becomes decompensated, consumption coagulation predominates and the other laboratory abnormalities listed are present (see above). Repetition at regular intervals of specific coagulation tests (see above), especially the platelet count, fibrinogen level, and D-dimer level, is critical. These tests provide a kinetic parameter that greatly aids in the assessment of the severity of the DIC and the choice of appropriate management.


Currently, management must be directed at the primary disease to switch off the initiating event. This approach may involve chemotherapeutic treatment of an underlying tumor, administration of antibiotics and surgical drainage of an abscess, or emptying the uterus when complications of pregnancy have been the inciting cause. Hemodynamic support is essential. The use of an-tifibrinolytic agents such as EACA or aprotinin is contraindicat-ed. Despite its bleeding complications, DIC is a severe hyperco-agulable state, and these agents block the fibrinolytic system and may exacerbate its thrombotic complications. The administration of blood products, such as platelets, fresh frozen plasma, or cryoprecipitate, may add fuel to the fire and worsen the consumption coagulopathy. However, if clinical bleeding becomes significant, it is prudent to give vigorous blood product support.

The use of heparin in cases of acute DIC has not been established. Although heparin, by activating antithrombin (AT), is effective in inhibiting thrombin and therefore should be efficacious in the treatment of DIC, its use is generally limited to situations of chronic or compensated DIC. Heparin, given subcutaneously, is effective in the treatment of venous thrombosis in patients with Trousseau syndrome. In the case of decompensated DIC, in which bleeding is the major clinical manifestation, heparin may significantly exacerbate the bleeding and is therefore generally not indicated. The use of high-dose AT infusion has been advocated in this situation, but its efficacy has not been established by randomized studies.

Recombinant human activated protein C (APC, or drotreco-gin alfa [activated]) has been shown to significantly reduce mortality in patients with severe sepsis (mortality was 24.7% in patients given APC versus 30.8% in patients given placebo).39 Although it is associated with a slightly increased risk of bleeding, APC appears to be an effective agent in the treatment of severe DIC in patients with sepsis, even for patients with normal protein C levels.40 In large randomized trials, neither recombinant tissue factor pathway inhibitor (TFPI) nor AT concentrate reduced mortality in septic patients.41,42 In cases of DIC associated with solitary or multiple hemangiomas, the hemangiomas can be excised when they are localized, and they occasionally show a good response to local irradiation. Attempts to control DIC associated with hemangiomas by the administration of heparin, cor-ticosteroids, aspirin, and estrogens have not been successful. The key to successful management of DIC associated with certain snakebites is identification of the type of snake and prompt administration of appropriate antivenin.

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