Hemostatic Disorders

GENERAL PRINCIPLES

• Normal hemostasis involves a sequence of interrelated reactions that lead to platelet aggregation (primary hemostasis) and activation of coagulation factors (secondary hemostasis) to produce a durable vascular seal.

î Primary hemostasis consists of an immediate but temporary response to vessel injury, where platelets and von Willebrand factor (vWF) interact to form a primary hemostatic plug.

î Secondary hemostasis results in formation of a fibrin clot (Figure 20-1). Injury exposes extravascular tissue factor to blood, which initiates activation of factors VII and X and prothrombin. Subsequent activation of factors XI, VIII, and V leads to generation of thrombin, conversion of fibrinogen to fibrin, and formation of a durable clot.¹

Figure 20-1 Coagulation cascade.Solid arrows indicate activation. Solid or dashed lines that run into a vertical line are associated with drugs represent a point of inhibition. Extrinsic pathway includes the right upper portion of cascade above factor X. Intrinsic pathway includes the left upper portion of the cascade above factor X. Common pathway includes the lower portion of the cascade from factor X and below. AT, antithrombin; LMWH, low-molecular-weight heparin; TF, tissue factor.

DIAGNOSIS

Clinical Presentation

• A detailed history can assess bleeding risk or severity, determine congenital or acquired etiologies, and evaluate for primary or secondary hemostatic defects.

î Prolonged bleeding after dental extractions, circumcision, menstruation, labor and delivery, trauma, or surgery may suggest an underlying bleeding disorder.

î Family history may suggest an inherited bleeding disorder.

PHYSICAL EXAMINATION

• Primary hemostasis defects often cause mucosal bleeding and excessive bruising.

î Petechiae: lt;2 mm subcutaneous lesions, do not blanch with pressure, typically present in areas subject to increased hydrostatic force (lower legs and periorbital area)

î Ecchymoses: gt;3 mm black-and-blue patches due to rupture of small vessels from trauma

• Secondary hemostasis defects can result in hematomas, hemarthroses, or prolonged bleeding after trauma or surgery.

Diagnostic Testing

LABORATORIES

• Initial studies should include a complete blood count (CBC) with platelet count, as well as prothrombin time (PT), activated partial thromboplastin time (aPTT), and a peripheral blood smear.

• Primary hemostasis tests

î A low platelet count requires review of the peripheral blood smear to rule out platelet clumping artifact or giant platelets as the cause of a falsely low platelet count.

î The platelet function assay-100 (PFA-100) instrument assesses vWF-dependent platelet activation in flowing citrated whole blood. Patients with von Willebrand disease (vWD) and qualitative platelet disorders can have prolonged PFA-100 closure times, often with normal platelet counts. However, anemia (hematocrit lt; 30%) and/or thrombocytopenia (platelet lt; 100 ? 10⁹#8725;L) can cause prolonged closure times without underlying bleeding disorders.

° In vitro platelet aggregation studies measure platelet secretion and aggregation in response to platelet agonists (see Qualitative Platelet Disorders section).

î Laboratory evaluation of vWD includes measurement of vWF antigen (vWF:Ag) and vWF activity and vWF multimer analysis.

• Secondary hemostasis (Figure 20-1)

î PT: Measures time to form a fibrin clot after adding thromboplastin (tissue factor and phospholipid) and calcium to citrated plasma. An elevated PT is a sensitive test of deficiencies of extrinsic pathway (factor VII), common pathway (factors X and V and prothrombin), and fibrinogen, and to use of vitamin K antagonists. Reporting a PT ratio as an international normalized ratio (INR) reduces interlaboratory variation in monitoring warfarin use.²

î aPTT: Measures the time to form a fibrin clot after activation of citrated plasma by calcium, phospholipid, and negatively charged particles.

î Thrombin time: Measures time to form a fibrin clot after addition of thrombin to citrated plasma. Unfractionated heparin, LMWH, fondaparinux, and direct thrombin (IIa) inhibitors prolong thrombin time, as do quantitative and qualitative deficiencies of fibrinogen and fibrin degradation products.

î Fibrinogen: Measured by adding thrombin to dilute plasma and measuring clotting time. Conditions causing hypofibrinogenemia include decreased hepatic synthesis, massive hemorrhage, and disseminated intravascular coagulation (DIC).

î d-dimers result from plasmin digestion of fibrin (i.e., fibrin degradation products). Elevated d-dimer concentrations occur in many disease states (i.e., venous thromboembolism [VTE], DIC, trauma, and cancer).

î Mixing studies determine whether a factor deficiency or an inhibitor has prolonged the PT and/or aPTT. In a patient with factor deficiency, mixing patient plasma 1:1 with normal pooled plasma (all factor activities = 100%) restores deficient factors sufficiently to normalize or nearly normalize the PT or aPTT (Table 20-1). If mixing fails to correct the PT or aPTT, a specific factor inhibitor, a nonspecific inhibitor (e.g., lupus anticoagulant [LA]), or an anticoagulant drug may have caused the prolongation.

TABLE 20-1

aPTT, activated partial thromboplastin time; HMWK, high-molecular weight kininogen; PK, prekallikrein; PT, prothrombin time.