Hemorrhagic and Thrombotic Disorders

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[edit] Hemorrhagic and Thrombotic Disorders

Jack E. Ansell

Primary care physicians often encounter clinical problems of bleeding or thrombosis. Easy bruising is a common complaint in the office setting. Posttraumatic or postsurgical bleeding in a hospitalized patient may first be seen by the family physician for management. Physicians are commonly faced with an unexpected or unexplained prolonged partial thromboplastin time or bleeding time. Deep venous thrombosis of a lower extremity, although a common medical condition, is notoriously tricky to diagnose, and its treatment may be fraught with complications. Accordingly, primary care physicians must have a working knowledge of the rudiments of hemostatic and thrombotic reactions, associated pathologic conditions, and especially appropriate treatment of disorders that can evolve into life-threatening emergencies. This discussion touches on a wide range of hemorrhagic and thrombotic disorders and their treatment, beginning with a brief overview of coagulation and platelet physiology.

[edit] NORMAL HEMOSTASIS

Normal hemostasis depends on the close interaction of platelets and the coagulation proteins in a normally functioning vascular system. As a consequence of vascular injury, platelets exposed to subendothelial collagen are stimulated to undergo a sequence of reactions leading to primary platelet plug formation. This plug is then reinforced by the activation of coagulation and fibrin formation to form a stable hemostatic plug.

Platelet reactions can be divided into three physiologic processes: adhesion to subendothelial collagen; activation, shape change, and secretion of a number of substances; and aggregation between adjacent activated platelets. Adhesion depends on specific platelet membrane receptors (glycoprotein Ib) and on von Willebrand's factor, a plasma factor that serves as a bridge between platelets and collagen. Deficiencies of either can lead to platelet dysfunction and bleeding. Platelet secretion depends on a sequence of reactions in the platelet membrane, which leads to calcium mobilization in the platelet cytosol, release of arachidonic acid, and the formation of thromboxane A₂. As a result, platelets secrete a number of endogenous proteins, platelet agonists, and vasoactive factors. This process also exposes the glycoprotein IIb-IIIa complex on the platelet membrane, which binds fibrinogen and serves as a linking site to bind other platelets and thus complete the process of platelet aggregation.

As platelets are activated, the coagulation cascade is also initiated, leading to fibrin formation and stabilization of the primary platelet plug (Fig. 115-1). A number of proenzymes require activation, while cofactors accelerate the enzymatic reactions, and inhibitors limit the reactions. Factors XII and XI in the intrinsic system are activated by contact with damaged endothelial cells. Kallikrein accelerates the reaction and high-molecular-weight kininogen serves as a cofactor. Factor IX in turn is activated by XIa but can also be activated through the extrinsic system by factor VII–tissue factor. Factor VIII is a cofactor accelerating the activation of factor X by IXa. Factor X can also be activated through the extrinsic system by factor VII and tissue factor. Factor VII is activated by the release or exposure of tissue factor from injured endothelial cells. The common pathway proceeds with activation of factor II (prothrombin), with factor V serving as a cofactor. Factor IIa, or thrombin, then cleaves two small peptides from fibrinogen (peptides A and B), and the remaining fibrin monomers polymerize to form long fibrin strands and ultimately a fibrin clot. Factor XIII stabilizes the association of fibrin monomers by introducing covalent disulfide bonds between strands.

Figure 115-1 Coagulation cascade. Fibrin clot formation results from the generation of thrombin, which is dependent on the sequential interaction of proenzymes and activated coagulation factors in the intrinsic, extrinsic, and common pathways of coagulation. HMW, High molecular weight;PL, phospholipid.

There are a number of natural inhibitors in this process serving to limit fibrin formation. These include antithrombin, heparin cofactor II, protein C, protein S, and tissue factor pathway inhibitor (Fig. 115-2). Deficiencies of any of these proteins can lead to hypercoagulable or prethrombotic conditions.

Figure 115-2 Coagulation cascade illustrating the site of action of coagulation inhibitors and the fibrinolytic system. AT, Antithrombin;PC/PS, protein C/protein S;t-PA, tissue plasminogen activator;PAI, plasminogen activator inhibitor;TFPI, tissue factor pathway inhibitor;PTF 1,2, prothrombin fragment 1,2;FDP, fibrin(ogen) degradation products.

Last, fibrin formation is limited by the fibrinolytic system, the principal factor being plasminogen (see Figs. 115-1 and 115-2). The primary activator of plasminogen is tissue plasminogen activator (t-PA) released from damaged endothelial cells. t-PA has its own natural inhibitor, plasminogen activator inhibitor, which can be altered in disease states.

[edit] DIAGNOSIS

There are a large number of assays of the functional status of the coagulation and platelet mechanisms, but many are relevant only to the coagulation specialist consulting in the evaluation of complex hemorrhagic or thrombotic disorders. The primary care physician, however, should be familiar with the usual screening tests and the conceptual approach to evaluating hemostatic disorders.

[edit] History and Physical Examination

The evaluation begins with the clinical history to determine whether a patient truly has a bleeding tendency based on history (if acute bleeding is not currently present), and whether it is congenital or acquired based on data such as family history, male or female occurrence, and childhood bleeding. Clues to a coagulation vs. platelet defect can also be discerned by noting the history of petechiae (platelet defects) or ecchymoses (coagulation defects). None of these historical elements is definitive, but they do help in the overall evaluation. A detailed medication history is imperative, particularly noting aspirin or nonsteroidal antiinflammatory agent use. Physical examination provides limited clues in this evaluation but may help support a platelet or coagulation defect by the presence of petechiae or ecchymoses. Furthermore, the presence of other abnormalities may indicate an underlying systemic illness associated with specific hemorrhagic or thrombotic disorders.

[edit] Laboratory Evaluation

The laboratory evaluation can be extensive, but the initial tests almost always include a prothrombin time (PT) and activated partial thromboplastin time (aPTT) for screening of the entire coagulation cascade, and a platelet count and bleeding time to screen for quantitatively and qualitatively normal platelets. The bleeding time has been shown not to be a good preoperative screening test to predict bleeding potential, but it is useful for evaluating suspected qualitative platelet defects. The platelet count is obviously useful to detect reduced or increased platelet numbers.Fig. 115-3 highlights the approach to evaluating an abnormal PT or aPTT and the diagnostic possibilities. A prolongation of either test can be the result of a coagulation factor deficiency or circulating inhibitor (antibody). The distinction between these two possibilities is made by performing a mixing assay with patient and normal plasma and repeating the abnormal test. A correction in the result suggests a factor deficiency, whereas no correction suggests an inhibitor. Factor assays or other tests can then be performed to further distinguish the abnormalities.

Figure 115-3 Approach to the evaluation of a prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), or thrombin time (TT).

Additional assays with which physicians should be familiar include a thrombin time (an indirect measure of fibrinogen) and assays of fibrin(ogen) degradation products (FDP) or D-dimers. A positive FDP assay can result from plasmin lysis of fibrinogen or fibrin, whereas a positive D-dimer indicates plasmin lysis of fibrin, an indicator that thrombin has been generated and has converted fibrinogen to fibrin (i.e., intravascular coagulation).

Clinicians should not feel reticent about seeking consultative help from a coagulation specialist when confronted with a hemorrhagic or thrombotic disorder. Given their usual complexity, these disorders may require extensive laboratory evaluation.Table 115-1 illustrates some of the more common disorders and how they would alter the usual screening tests just discussed.

Table 115-1 Presumptive Diagnosis of Common Bleeding Disorders Based on Routine Screening Tests

[edit] HEMORRHAGIC DISORDERS AND THEIR TREATMENT

[edit] Thrombocytopenia

A prolonged bleeding time as a result of thrombocytopenia does not develop until the platelet count reaches the 50,000 to 75,000/μl range (normal 150,000 to 350,000/μl). The risk of significant spontaneous bleeding, however, is not present until the count reaches the 10,000 to 20,000/μl level. Furthermore, the risk of bleeding is somewhat less for the same level of platelet count when the thrombocytopenia is due to peripheral destruction vs. inadequate production of platelets as determined by bone marrow biopsy.

Inadequate production of platelets may result from a stem cell defect and usually affects all three cell lines, as in the myeloproliferative and myelodysplastic syndromes. Invasion of the marrow by carcinoma, granuloma, or fibrosis also interferes with thrombopoiesis. Cancer chemotherapy is probably the most common cause today for a drug-induced reduction in platelet production, although some other drugs can also interfere, usually in an idiosyncratic fashion. Vitamin B₁₂ and folic acid deficiencies are well-known causes of ineffective thrombopoiesis. Platelet transfusions are indicated to treat bleeding in these situations, but prophylactic platelets are not generally recommended unless the platelet count is reduced to the 5,000 to 10,000/μl range. When platelets are transfused, the quantity obtained from a single apheresis donor is used, which is equivalent to the platelets obtained from approximately 6 to 8 random donor units. Alternatively, random donor platelets can be used.

Thrombocytopenia in the setting of a normal bone marrow can be attributed to either immune or nonimmune peripheral destruction, and rarely to excessive dilution. Nonimmune thrombocytopenia is most often encountered with disseminated intravascular coagulation (DIC), where platelets are activated and destroyed when they come in contact with intravascular fibrin or are exposed to thrombin (see Disseminated Intravascular Coagulation). Severe thrombocytopenia can also occur in the rare disorder of thrombotic thrombocytopenic purpura (TTP), a primary disorder of platelet consumption. The TTP syndrome consists of thrombocytopenia, microangiopathic hemolytic anemia, often transient neurologic deficits, renal impairment, and fever. TTP, once a highly fatal disorder, is responsive to the simultaneous administration of fresh frozen plasma (FFP) and plasmapheresis. High-dose adrenal corticosteroids may provide some benefit, and in some cases splenectomy may also be of benefit. With these treatments mortality has been reduced considerably, but TTP and DIC are still life-threatening emergencies that require hematologic consultation.

Immunologic thrombocytopenia may be mediated by drug-induced antibodies, isoantibodies, or autoantibodies. Drug-induced antibodies may attach to platelet membranes by an innocent bystander mechanism (immune complex deposition), in response to neoantigen formation by a drug and platelet membrane complex, or by specific membrane receptor targeting induced by a drug. Heparin is the most common cause of drug-induced thrombocytopenia. Heparin-induced thrombocytopenia (HIT) usually occurs after 6 to 8 days of intravenous heparin therapy, although it can occur sooner, especially in patients recently exposed to heparin, and it may develop after exposure to subcutaneous therapy or even heparin flushes used to maintain catheter patency. It is an immune-mediated thrombocytopenia. The diagnosis is based on the clinical presentation with other causes being excluded. Heparin-induced platelet aggregation or serotonin release assays may help confirm a diagnosis, but are rarely useful in managing the acute situation because of limited availability or prolonged turnaround.

Although platelet counts may be low, bleeding is unusual. Rather, paradoxical thromboembolism is the most worrisome complication and may be attributable to in vivo heparin-induced platelet aggregation. HIT occurs in about 1% to 5% of patients taking heparin for 5 to 10 days, and heparin-induced thrombosis occurs in one third to one half of these patients. Cessation of heparin is mandatory, and alternative anticoagulation is initiated with either a low-molecular-weight heparinoid called danaparoid (Orgaran) or a recently approved hirudin derivative called lepirudin (Refludan). Substitution with one of the low-molecular-weight heparin products is contraindicated because of the high cross reactivity of the heparin-induced platelet antibody.

Idiopathic (immune) thrombocytopenic purpura (ITP) is the most common form of immunologic thrombocytopenia. It occurs in acute (often in children) and chronic (in adults) forms. In children 90% or more of cases have an acute onset, often preceded by a viral illness, and resolve on their own over the course of 1 to 3 months. Physical findings are limited to the skin, where petechiae may be seen, especially in the dependent extremities. Splenomegaly is not seen. Specific treatment is often unnecessary, although corticosteroids may be given to boost the count from very low levels until spontaneous recovery occurs. ITP in the adult is most often chronic with an insidious onset of easy bruising or minor bleeding noted over the preceding months. Women are more commonly affected. Bleeding manifestations include petechiae, ecchymoses, menorrhagia, hematuria, melena, epistaxis, and gingival bleeding. The onset is not associated with an antecedent infection. The physical examination is unremarkable. The diagnosis is traditionally based on clinical grounds (i.e., the exclusion of other causes of thrombocytopenia in the setting of peripheral destruction of platelets as determined by a bone marrow biopsy). A platelet antibody assay may be helpful but should not be used as a definitive test. Treatment is more complex than for childhood ITP. Corticosteroids are indicated initially, but definitive responses are uncommon. Splenectomy is generally indicated next in low-surgical-risk candidates. Other treatment modalities include intravenous γ-globulin, attenuated androgens, immunosuppressive agents, staphylococcal protein A columns, and plasmapheresis. After all therapeutic modalities are exhausted, about 10% of patients continue to have serious thrombocytopenia for which no therapy is effective.Table 115-2 highlights the differences between the acute and chronic forms of ITP.

Table 115-2 Clinical Features of the Acute and Chronic Forms of Idiopathic Thrombocytopenic Purpura

Thrombocytopenia resulting from isoantibodies occurs after multiple platelet transfusions, or in a syndrome called posttransfusion purpura caused by transfusion of mismatched platelets. Thrombocytopenia can also occur on a dilutional basis in individuals transfused large volumes of blood over a short interval (e.g., 10 to 20 units of blood over a 24-hour period). Finally, thrombocytopenia can occur as a result of a hyperfunctioning spleen (hypersplenism) in individuals with splenomegaly for a variety of reasons.

[edit] Qualitative Platelet Disorders

Functional platelet defects produce a long bleeding time in the presence of a normal platelet count and may predispose to bleeding. Inherited disorders are uncommon, the most likely one being von Willebrand's disease, which is a defect or deficiency in von Willebrand's factor, a component of the factor VIII complex that is important for normal platelet adhesion. Acquired defects are much more common and are usually the result of drugs, aspirin being the major offender. Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) impair platelet prostaglandin production and induce a release defect; aspirin-induced impairment is irreversible, whereas NSAID effect is not. Rarely platelet transfusions are needed to correct an aspirin defect in the face of serious bleeding. Uremia also produces a qualitative defect that can sometimes be improved by dialysis or by the infusion of cryoprecipitate or the use of deamino-8-d-arginine vasopressin (DDAVP). Last, myeloproliferative disorders can be associated with a platelet defect resulting from an abnormal stem cell.

[edit] Acquired Coagulation Disorders

A discussion of the inherited coagulation disorders is a pediatric topic, but the more common acquired disorders are important to review, since the primary care physician will be called upon to diagnose and treat these problems. The reader is referred to other texts listed at the end of the chapter for a more detailed discussion of the congenital factor deficiencies.

[edit] Vitamin K Deficiency.

Vitamin K deficiency is most often seen in seriously ill patients, especially in the postoperative state when patients are poorly nourished and receiving antibiotics. Poor nutrition removes vitamin K from the diet, and antibiotics suppress gut bacteria that produce vitamin K. Vitamin K deficiency produces an initial rise in the prothrombin time because of the rapid decline of factor VII activity, the vitamin K–dependent factor with the shortest metabolic half-life. An elevation of the activated partial thromboplastin time follows as other vitamin K–dependent factors decline (factors IX, X, and II). This condition, which often leads to serious bleeding, is easily reversed by parenteral vitamin K₁ therapy (5 to 10 mg subcutaneous).

[edit] Liver Disease.

Impairment of the synthetic capacity of the liver is one of the most common causes for an acquired hemostatic defect. Hemostatic failure usually reflects the degree of liver failure and is usually subtle in acute liver failure unless the destruction of parenchymal tissue is fulminant. The PT, dependent on the short 6-hour half-life of factor VII, is prognostically helpful. Patients with biliary tract disease and obstructive jaundice may also develop a coagulopathy, but the mechanism in this situation is closely linked to levels of the vitamin K–dependent coagulation factors resulting from impaired absorption of vitamin K.

Hemostatic failure in liver disease involves both the platelet and coagulation phases of clotting. Mild thrombocytopenia is frequently encountered because of hypersplenism that accompanies portal hypertension. Qualitative defects in platelet function are probably not a major factor.

Coagulation is impaired primarily because of decreased factor synthesis, but abnormal factors may be produced, excessive consumption can occur, and fibrinolysis may be enhanced as contributing causes of hemostatic failure. A low fibrinogen, one of the last factors to be reduced, is a poor prognostic sign.

Treatment depends on the severity of the coagulopathy and the presence of bleeding and usually includes FFP. Treatment simply for the purpose of correcting an abnormal PT and aPTT, however, is not recommended, since it takes a large volume of plasma to correct the abnormality, the correction is short lived, and the protein load contained in the plasma may be enough to induce hepatic encephalopathy in a patient who is so predisposed. Platelet transfusions can be given in the face of clinically important bleeding with a very low platelet count, but generally they are not indicated in hypersplenism.

[edit] Disseminated Intravascular Coagulation.

DIC often occurs in critically ill patients and is common in the intensive care setting. However, DIC can also occur in relatively well patients, a result of certain underlying diseases such as malignancy. Its onset can be fulminant and rapidly fatal or can be more subtle and gradual. Although its name implies a disorder of intravascular clotting, its clinical expression is often one of a diffuse hemorrhagic disorder.

DIC involves the pathologic activation of coagulation by an underlying disease process that leads to fibrin clot formation and secondary fibrinolysis, which then cause further consumption of coagulation factors, platelets, and red cells. In the fulminant syndrome bleeding results from factor deficiency (primarily factors I, II, V, VIII, and XIII), thrombocytopenia, excessive fibrinolysis, and high levels of FDP superimposed on a vascular system already damaged by diffuse microvascular thrombi. Bleeding is typically manifested by diffuse superficial hemorrhage in the form of ecchymoses and petechiae as well as oozing from the gingiva, the oral mucosa, or the gastrointestinal and urinary tracts. Most hemorrhage tends to be from the microvasculature, although major vascular hemorrhage and central nervous system bleeding can occur.

The pathophysiology of the consumption process depends on the underlying disease process or initiating event. The common mechanism is activation of a pathway of coagulation, usually the tissue factor pathway.Box 115-1 summarizes those conditions likely to cause a DIC syndrome.

The diagnosis of DIC is complicated by the fact that the clinical manifestations range from no findings to those of an extensive thrombotic or hemorrhagic disease. Bleeding is usually generalized and from the microvasculature.Table 115-3 highlights those tests commonly used to diagnose DIC. The most important component in the treatment of DIC is correction of the underlying disease. Supportive measures include FFP and platelet transfusions. Recent studies suggest a benefit to infusions of antithrombin concentrates, but it is too premature to recommend their use. In rare cases low doses of intravenous or subcutaneous heparin may be useful to interrupt the process of consumption by neutralizing activated coagulation factors. This may be most helpful in well-characterized conditions such as acute promyelocytic leukemia associated with a high incidence of DIC. Efficacy of therapy can be monitored by looking for a decrease in FDP, or D-dimer, an increase in fibrinogen, or the normalization of the PT and aPTT.

Table 115-3 Laboratory Findings in Disseminated Intravascular Coagulation

[edit] THROMBOTIC DISORDERS AND THEIR TREATMENT

The evaluation of an individual with thrombosis or suspected of having an increased risk of thrombosis should focus on abnormalities of one of the three elements of Virchow's triad—blood vessels, blood flow, or blood constituents. In the search for the etiology of a thrombotic event it is essential to take into account factors known to enhance the risk of thrombosis (Box 115-2). When a primary disorder of coagulation is the suspected cause, one begins by measuring the activities of the principal inhibitors of coagulation, including antithrombin, protein C, and protein S. Recently described genetic abnormalities of Factor V (Factor V_Leiden), leading to resistance to protein C inactivation, and prothrombin²⁰²¹⁰, leading to increased circulating prothrombin, are relatively common causes of hypercoagulability and are found in as many as 6% or 3%, respectively, of the white population in the United States. Fibrinolytic system disorders can also be investigated. Analysis is best done when the acute thrombotic episode has stabilized and ideally when the patient is not receiving anticoagulants.

[edit] Antithrombotic Therapy

The following discussion focuses on the major antithrombotic agents in clinical use. Discussion of the various thromboembolic syndromes can be found elsewhere in this text.

[edit] Anticoagulants

[edit] Heparin.

Heparin is a glycosaminoglycan of heterogeneous molecular weight derived from porcine intestinal mucosa or bovine lung. Heparin causes its anticoagulant effect through high-affinity binding with circulating antithrombin (AT). Binding with heparin produces a conformational change of AT, which greatly accelerates its inactivation of coagulation factors Xa, IXa, and thrombin, thereby causing a rapid anticoagulant effect.

Heparin is given parenterally as a constant intravenous infusion. Heparin dosing nomograms have recently been shown to provide for a more rapid achievement of therapeuticanticoagulation, and their use is recommended (Table 115-4). Heparin may also be given by intermittent intravenous bolus at 4-hour intervals, but such therapy has been shown to be less effective than continuous infusions.

Table 115-4 Guidelines for Dosing Heparin According to a Weight-based Nomogram

✢The therapeutic range will vary depending on the aPTT reagent in use. Each laboratory must perform its own in vitro heparin titration curve to establish the therapeutic range for the specific aPTT reagent in use that is equivalent to a heparin concentration of 0.2-0.4 U/ml.

When heparin is given intravenously, the intensity of anticoagulation is monitored using the aPTT. The heparin infusion is adjusted to prolong the aPTT to the recommended therapeutic range depending on the aPTT reagent. Reagent differences can be overcome by performing in vitro heparin titration curves to determine the correlation of the aPTT with therapeutic heparin concentrations in the range of 0.2 to 0.4 U/ml. The overall variability of response to heparin demands frequent monitoring of the aPTT while treatment with heparin proceeds. Physicians encounter considerable variability in patients' heparin requirements not only because of differences in aPTT reagent sensitivity to heparin, but also because of differences in heparin clearance and neutralization by heparin-binding proteins.

Bleeding is the most common adverse effect of heparin therapy and is influenced by anticoagulation intensity, duration of heparin therapy, concomitant use of other drugs, and severity of illness. Heparin anticoagulation may be rapidly reversed with protamine sulfate, given at a ratio of 1 mg per 100 U of estimated heparin reserve (the amount of heparin thought to remain in the body). Heparin-associated thrombocytopenia occurs in approximately 1% to 5% of patients receiving heparin and is occasionally associated with venous and arterial thrombosis and bleeding (see discussion of heparin-induced thrombocytopenia earlier in this chapter). Chronic subcutaneous heparin therapy may cause osteoporosis in a minority of patients, leading to spontaneous fractures. Heparin does not cross the placenta and may be used for thromboembolic treatment during pregnancy.

[edit] Low-molecular-weight Heparin.

Low-molecular-weight heparins (LMWHs) are obtained by enzymatic or chemical depolymerization of unfractionated heparin. They have a more uniform distribution by molecular weight and shorter chain length of polysaccharides, with an average molecular weight of 4500 to 6000. LMWHs are advantageous compared with standard heparin in their greater ability to neutralize factor Xa compared with thrombin. They have less binding to heparin-binding proteins and platelets, have a longer half-life, are more uniformly absorbed from subcutaneous depots, and cause less heparin-induced thrombocytopenia. They can be given subcutaneously once or twice daily depending on the indication and the preparation. Dosages are determined on a fixed or weight basis and do not require monitoring, at least when used for primary prophylaxis. Several LMWH preparations are FDA approved in the United States for different prophylactic indications and for treatment of venous thromboembolism. One must become familiar with the different preparations and use them by name since dosage and indications vary. The differences between LMWH and regular heparin and the advantages of LMWH are illustrated in Table 115-5.

Table 115-5 Advantages of Low-molecular-weight Heparin

[edit] Oral Anticoagulants (Warfarin).

Patients requiring intermediate-term or chronic anticoagulation are treated with warfarin, the most widely used oral anticoagulant.

Warfarin exerts its anticoagulant effect through competitive interference with vitamin K, which is essential for the normal synthesis of factors II, VII, IX, and X, and the antithrombotic factors protein S and protein C. Vitamin K serves as a cofactor that catalyzes the γ-carboxylation ofcertain glutamic acid residues on the vitamin K–dependent coagulation factors; the reaction provides critical calcium binding sites essential for full function. By competitive inhibition of microsomal reductases warfarin interferes with the conversion of oxidized vitamin K to its active reduced form, causing an acquired vitamin K deficiency and hepatic production of functionally inactive coagulation factors. Because the half-lives of the vitamin K–dependent factors vary, the full effect of a given dose of warfarin on the PT is not seen for several days after initiation of therapy. Early prolongation of the PT is due to depletion of factor VII, which has an estimated half-life of 6 to 8 hours.

Conversely, treatment with intravenous vitamin K reverses warfarin-induced anticoagulation via synthesis of new vitamin K–dependent factors within 24 to 48 hours. When necessary, treatment with intravenous FFP gives a rapid (although temporary) reversal of warfarin effect by direct replacement of active vitamin K–dependent factors.

Warfarin therapy is usually initiated with a dosage of 5 to 10 mg, with subsequent doses based on the response of the international normalized ratio (INR). When heparin anticoagulation precedes warfarin therapy, treatment with warfarin should begin 3 to 5 days before termination of heparin to permit full depletion of vitamin K–dependent factors and achieve a therapeutic PT. Usually both heparin and warfarin can be started at the same time when a patient enters the hospital with a deep venous thrombosis or pulmonary embolism.

The INR is the standard reporting methodology for monitoring warfarin anticoagulation; earlier monitoring methods using the PT fail to correct for differences in reagent sensitivity, and thus PTs from different laboratories are not comparable. The INR provides a method to compare different PTs based on an international standard. It is calculated by raising the laboratories' PT ratio (PT) mean normal range) to the power expressed by the international sensitivity index, a measure of thromboplastin reagent sensitivity. Two intensity levels of warfarin anticoagulation are currently recommended: less intense warfarin therapy (INR of 2 to 3) is sufficient for most thromboembolic indications, and more intense warfarin therapy (INR of 2.5 to 3.5) is reserved for mechanical heart valves and failure of less-intensive treatment with warfarin (Table 115-6). During warfarin treatment the patient's INR must be monitored regularly to ensure the desired intensity of anticoagulation. After initiating therapy the INR is checked at least weekly, adjusting the warfarin dose when necessary. When stable anticoagulation is attained, the frequency of INR testing may be reduced, based on the patient's compliance with medication and follow-up. Compliance can be improved significantly with regular education about warfarin dosing, drug interactions, and potential side effects of warfarin therapy.

Table 115-6 Therapeutic Range for Oral Anticoagulant Therapy Based on the International Normalized Ratio

Variations in dietary vitamin K, drug interactions with warfarin, and patient compliance all may cause rapid fluctuations in response to a given warfarin dose. Physicians must be aware of the many potential drug interactions with warfarin and should avoid those medications known to alter warfarin's anticoagulant effect. As a precaution, anticoagulated patients starting a new medication should be monitored with more frequent INR testing to detect any changes in anticoagulant effect induced by the drug.

Bleeding is the most frequent side effect of warfarin therapy. The risk increases with greater intensity of anticoagulation, history of previous bleeding, concurrent use of antiplatelet agents, severe intercurrent illness, and old age. Bleeding during warfarin anticoagulation may unmask occult pathology, such as lung, colon, uterine, or bladder neoplasia. Physicians must consider obtaining appropriate diagnostic studies if anticoagulated patients develop hemoptysis, rectal or vaginal bleeding, or hematuria. Warfarin-induced skin necrosis is a rare complication caused by thrombosis of small vessels supplying subcutaneous fat, often associated with occult protein C or protein S deficiency. Warfarin is contraindicated during pregnancy because of fetal bleeding and multiple teratogenic effects. Women of childbearing age who require warfarin therapy should be counseled in effective methods of birth control, and a pregnancy test is a prudent precaution for such patients before beginning treatment with warfarin.

[edit] Antiplatelet Agents

[edit] Aspirin.

Aspirin and most other NSAIDs inhibit platelet aggregation by interfering with cyclooxygenase, an enzyme important in the generation of prostaglandins. Aspirin irreversibly inhibits this enzyme, whereas NSAIDs usually cause reversible inhibition of cyclooxygenase. Only small doses of aspirin are needed (less than one 5-grain tablet) to affect most of the platelets in the circulation. This effect persists for the lifetime of those platelets affected (about 10 days). Nonacetylated forms of salicylate (e.g., choline, sodium salicylate) do not have this inhibitory effect. Dipyridamole and sulfinpyrazone, agents used in the past for their supposed antiplatelet effect, have been shown not to have any beneficial effect mediated by antiplatelet activity.

[edit] Ticlopidine and Clopidogrel.

Ticlopidine and clopidogrel are similarly acting antiplatelet agents that mediate their effect by inhibiting the adenosine diphosphate pathway for platelet activation. Their onset of action is slow, with a cumulative effect over 8 to 10 days and a similar time for recovery of platelet function once discontinued. Ticlopidine was the first of these two agents that was shown to be an effective platelet inhibitor in a number of conditions, but its use has been limited because of potentially serious side effects, including neutropenia and a syndrome of thrombotic thrombocytopenic purpura. More recently clopidogrel has been available as an agent with effective antiplatelet properties and a reasonable substitute for individuals unable to take aspirin.

[edit] Thrombolytic Agents.

The major fibrinolytic or thrombolytic agents currently in use include streptokinase, urokinase, t-PA, and anisoylated plasminogen-streptokinase activator complex (APSAC or anistreplase). These agents are most often used in ischemic cardiovascular disease (see Chapter 63 ). They are also recommended in fulminant pulmonary embolism and some cases of deep venous thrombosis, but because of a high-risk profile they should be used with great care and in those with no risk factors for bleeding. At a minimum, these agents are contraindicated in the setting of active internal bleeding, recent (within 2 months) cerebral vascular event or intracranial/intraspinal surgery, intracranial neoplasm, arteriovenous malformation or aneurysm, severe uncontrolled hypertension, or a known bleeding diathesis. Thrombolytic agents are used for the clearance of thrombi that obstruct indwelling catheters such as those used in cancer patients.

Streptokinase, the least expensive agent, binds to plasminogen, and the streptokinase-plasminogen complex activates other plasminogen molecules to the active enzyme plasmin. Urokinase directly activates plasminogen. t-PA, which also activates plasminogen directly, has a greater affinity for clot-bound plasminogen than circulating plasminogen and thus is less likely to activate plasminogen in a systemic fashion, leading to hypofibrinogenemia. However, in the dosages needed to be effective, some of this specificity is lost. Through molecular manipulation anistreplase has greater affinity for fibrin than circulating fibrinogen and thus on a theoretic basis is less likely to produce systemic hypofibrinogenemia. It also has a longer half-life than the three other agents.

Thrombolytic therapy does not require close monitoring of coagulation parameters, since a fixed dosage is given in most situations. The major reason to monitor therapy in some cases is to ensure that a lytic state has been achieved; this can easily be determined by a thrombin time that should be at least 3 seconds above baseline value or a fibrinogen level that should be reduced to the 1.5 gm/L level. Streptokinase has the problem of being susceptible to neutralization by existing antistreptococcal antibodies as well as producing allergic reactions resulting from these antibodies. It is recommended to coadminister corticosteroids with streptokinase to prevent such reactions, and if a lytic state cannot be achieved, another thrombolytic agent should be used.Table 115-7 summarizes the recommended dosages of these agents for their currently approved indications.

Table 115-7 Approved Indications and Suggested Dosages for Thrombolytic Agents

[edit] ADDITIONAL READINGS

• American Society of Hematology ITP Practice Guideline Panel: Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. Ann Intern Med 1997; 126:319 - 326.
• J Ansell: Oral anticoagulant therapy: fifty years later. Arch Intern Med 1993; 153:586.
• RL Bick: Platelet function defects: a clinical review. Semin Thromb Hemost 1992; 18:167.
• GJ Broze: The role of tissue factor pathway inhibitor in a revised coagulation cascade. Semin Hematol 1992; 29:159.
• LH Clouse, PC Comp: The regulation of hemostasis: the protein C system. N Engl J Med 1986; 314:1298.
• J Hirsh: Heparin. N Engl J Med 1991; 324:1565.
• SC Landefeld, RJ Beyth: Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993; 95:315.
• DA Lane, PM Mannucci, KA Bauer,et al.: Inherited thrombophilia: Part I. Throm Hemostas 1996; 76:651 - 662.Part II 76:824-834
• RA Raschke,et al.: The weight-based heparin dosing nomogram compared with a "standard care" nomogram. Ann Intern Med 1993; 119:874.
• I Redei, RN Rubin: Recognizing the most common causes of bleeding in the ICU: how to diagnose and treat platelet and coagulation disorders. J Crit Illness 1995; 10:121 - 132.133-137
• AH Schmaier: Disseminated intravascular coagulation: pathogenesis and management. J Intens Care Med 1991; 6:209.
• JH Stein, PE McBride: Hyperhomocysteinemia and atherosclerotic vascular disease. Arch Intern Med 1998; 158:1301 - 1306.
• JI Weitz: Low molecular weight heparins. N Engl J Med 1997; 337:688 - 698.