Chapter 232: Tests of Hemostasis

Most bleeding seen in the ED is a result of trauma—local wounds, lacerations, or other structural lesions—and the majority of traumatic bleeding occurs in patients with normal hemostatic mechanisms.¹ In these patients, specific assessment of hemostasis is unnecessary. However, some ED patients have abnormal bleeding due to impaired hemostasis. Identifying these patients requires attention to the history and physical findings.^2,3,4 Generally speaking, when patients have spontaneous bleeding from multiple sites, bleeding from untraumatized sites, delayed bleeding several hours after trauma, and bleeding into deep tissues or joints, the possibility of a bleeding disorder should be considered.

Important historical data that aid in identifying a congenital bleeding disorder include the presence of unusual or abnormal bleeding in the patient and other family members and any occurrence of excessive bleeding after dental extractions, surgical procedures, or trauma.⁵ Many patients with abnormal bleeding have an acquired disorder, such as liver disease, renal disease, or drug use (particularly ethanol, aspirin, nonsteroidal anti-inflammatory drugs, antiplatelet drugs, oral anticoagulants, antibiotics, and other salicylate-containing products).^2,3,4 Many supplements and herbal preparations, including garlic, ginseng, ginkgo biloba, ginger, and vitamin E, can also increase bleeding tendencies.

The site of bleeding may provide an indication of the hemostatic abnormality. Mucocutaneous bleeding, including petechiae, ecchymoses, epistaxis, GI or GU bleeding, or heavy menstrual bleeding, is characteristic of qualitative or quantitative platelet disorders. Purpura is often associated with thrombocytopenia and commonly indicates a systemic illness. Bleeding into joints and potential spaces, such as between fascial planes and into the retroperitoneum, and delayed bleeding are most commonly associated with coagulation factor deficiencies. Patients who demonstrate both mucocutaneous bleeding and bleeding in deep spaces may have disorders such as disseminated intravascular coagulation, in which both platelet abnormalities and coagulation factor abnormalities are present (see chapters 233, "Acquired Bleeding Disorders," 234, "Clotting Disorders," and 235, "Hemophilias and von Willebrand's Disease").

Common laboratory tests for hemostasis have their limitations.^6,7 They are generally useful and reliable for identifying disorders of coagulation factor function and quantitative platelet availability. However, tests of qualitative platelet function show a significant biologic variation, so that standardization has been difficult to achieve.^8,9 In addition, liver disease and renal failure—two conditions that increase the potential for abnormal hemorrhage—may not give rise to consistent and measurable abnormal results on routine tests of hemostasis.^10,11,12

Presentation of a patient to the ED with a disorder due to an intravascular thrombosis, such as a deep venous thrombosis or pulmonary embolus, suggests the potential for an underlying hypercoagulable state (see chapter 234). Premature coronary artery disease and acute coronary syndrome in individuals as young as teenagers have also been linked to hypercoagulable conditions. However, many, if not most, occurrences of intravascular thrombosis are not due to exaggerated hemostasis, but rather are due to local conditions, with blood vessel wall injuries, local inflammation, or vascular stasis provoking the thromboembolic event.^13,14

The susceptibility to hypercoagulation may be acquired or genetically transmitted. Common acquired hypercoagulable disorders include essential thrombocythemia, polycythemia vera, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, and cancer (often occult at the time of acute thrombosis). Inherited hypercoagulable disorders include factor V Leiden, prothrombin mutations, hyperhomocysteinemia, and deficiencies of protein C, protein S, and antithrombin. Patients with inherited hypercoagulable conditions tend to have venous thrombosis, whereas those with acquired disorders can have both arterial and venous clots.

Proteins C and S are vitamin K–dependent antihemostatic factors made in the liver, associated with disorders leading to deficiencies of these proteins inherited in an autosomal manner. Protein C is activated by thrombin and functions with protein S to stop fibrin formation and to stimulate the process of fibrinolysis. Antithrombin is also an antihemostatic protein that blocks activated coagulation factors. Elevated homocysteine level is also a known risk factor for thromboembolism.

Laboratory tests for a hypercoagulable diathesis show wide biologic variation, and standardization among laboratories has been difficult to achieve. The clinical utility of testing patients for suspected hypercoagulable conditions is dependent on the specific disorder.^13,14,15

The normal hemostatic system consists of a complex process that limits blood loss through the formation of a platelet plug (primary hemostasis) and the production of cross-linked fibrin (secondary hemostasis), which strengthens the platelet plug. These reactions are counterregulated by the fibrinolytic system, which limits the size of the fibrin clot that is formed and thereby prevents excessive clot formation. Congenital and acquired abnormalities occur in all these systems. The affected patient may have excessive hemorrhage, excessive thrombus formation, or both.

PRIMARY HEMOSTASIS

Primary hemostasis is the platelet interaction with the vascular subendothelium that results in the formation of a platelet plug at the site of injury. Required components for this to occur are normal vascular subendothelium (collagen), functional platelets, normal von Willebrand factor (connects the platelet to the endothelium via glycoprotein Ib), and normal fibrinogen (connects the platelets to each other via glycoprotein IIb and IIIa) (Figure 232-1). Primary hemostasis begins within 20 seconds of injury, is short-lived, and requires secondary hemostasis for clot stabilization.

SECONDARY HEMOSTASIS

Secondary hemostasis consists of the tightly regulated reactions of the plasma coagulation proteins. The final product is cross-linked fibrin, which is insoluble and strengthens the platelet plug formed in primary hemostasis (Figure 232-2).

Secondary hemostasis is also known as the coagulation cascade. The inactivated coagulation proteins (factors) are identified by Roman numerals, and after activation, the activated factor is designated by a. There are two independent activation pathways. The contact system is known as the contact activation pathway or intrinsic pathway, and the tissue factor system is known as the tissue factor pathway or extrinsic pathway. The pathways merge at the point of activation of factor X. Medications such as rivaroxaban (Xarelto^®) and apixaban (Eliquis^®) inhibit the activity of factor Xa. The combination of factor Xa, factor Va, phospholipid, and calcium ("thrombinase complex") more efficiently catalyzes the conversion of prothrombin to thrombin than free factor Xa. In turn, thrombin catalyzes the conversion of fibrinogen to fibrin monomer. Medications such as bivalirudin (Angiomax^®) or dabigatran (Pradaxa^®) are direct thrombin inhibitors. The common pathway describes the steps from factor X activation to cross-linked fibrin formation.

The fibrinolytic system regulates the hemostatic mechanism by limiting the size of the fibrin clots that are formed (Figure 232-3). Tissue plasminogen activator (tPA), released from endothelial cells, is the principal physiologic trigger for the fibrinolytic process, converting plasminogen, synthesized in the liver and adsorbed in the fibrin clot, to plasmin. Plasmin degrades fibrinogen and fibrin monomer into low-molecular-weight fragments known as fibrin degradation products and degrades cross-linked fibrin into d-dimers.

Other physiologic inhibitors of hemostasis with clinical relevance include antithrombin and the protein C–protein S system. Antithrombin is a protein that forms complexes with all the serine protease coagulation factors (factors XIIa, XIa, Xa, IXa, and thrombin), thereby inhibiting their function. Heparin potentiates this interaction, and this is the basis for its use as an anticoagulant. Proteins C and S are vitamin K–dependent factors that are produced in the liver. Activated protein C binds to the cell-surface-bound protein S, and this complex is capable of inactivating the two plasma cofactors factors Va and VIIIa and inhibiting their participation in the coagulation cascade. A single amino acid substitution in factor V, a condition named factor V Leiden, prevents activated protein C from binding and inhibiting the activity of factor Va. Thus, patients with this inherited condition have prolonged thrombogenic factor Va activity. Factor V Leiden, deficiency or defects in antithrombin, protein C, and protein S produce a potentially hypercoagulable condition and predispose the patient to venous thromboses.

Before embarking on a sequence of hemostatic testing, evaluate the patient in three areas: (1) Is the bleeding abnormal? (2) Is there a current medical condition associated with increased hemorrhage? (3) Is there a structural cause that explains the bleeding?^{13,14,15,16,17}

The basic laboratory tests obtained for a patient with a suspected abnormal bleeding disorder are a CBC and platelet count, prothrombin time, and activated partial thromboplastin time (Table 232-1). The results of these tests, coupled with clinical evaluation, should enable formulation of a differential diagnosis.¹⁸ Additional studies are ordered as indicated (Table 232-2). Obtain hematologic consultation if the differential diagnosis or the laboratory approach is unclear. In patients with postoperative bleeding, the basic laboratory tests for coagulation are of little help in assessment or management.¹⁹