Risk Stratification

Rapaport devised the following four-level stratification scheme to determine the need for preoperative laboratory testing according to the patient’s clinical status and bleeding history, and the planned operation²:

A properly drawn blood sample is paramount to interpreting the results of clotting tests. Whole blood is collected into an evacuated sample tube containing a fixed amount of citrate as an anticoagulant. The ratio of whole blood to citrate solution should be 9 : 1. An adult sample tube should be filled to at least 60% to 80% of its full collection volume to avoid excessive anticoagulation (a pediatric sample tube needs to be filled to 90% of its volume).⁴ The anticoagulated blood should be mixed gently by being inverted three to four times. Testing should be done within 2 hours if the sample is kept at room temperature and within 4 hours if kept at 4° C. Table 37-1 summarizes the screening tests used to determine the cause of coagulopathy.

The specifics of the pathways and assays pertinent to prothrombin time, activated partial thromboplastin time, thrombin time, activated clotting time, and thromboelastography are well described in Chapter 34 (in the section “Blood Coagulation Monitoring”). Thus they are described only briefly here.

von Willebrand Disease

von Willebrand factor (vWF) plays an important role in primary hemostasis by binding to both platelets and endothelial components, effecting formation of an adhesive bridge between them. vWF also contributes to clot formation by acting as a carrier protein for factor VIII.⁹

von Willebrand disease is the most common inherited bleeding disorder. Although it affects about 1% of the population, only 5% of affected patients are symptomatic.¹⁰ Clinical manifestations range from nil to severe bleeding, depending on the level of functional, circulating vWF. Easily identifiable but nonspecific symptoms include easy bruising, mucous membrane bleeding, prolonged epistaxis, postoperative bleeding, gastrointestinal bleeding, and heavy menstrual bleeding.^11,12 Previously undiagnosed patients sometimes have the first manifestation of the disease after taking antiplatelet agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin.

vWD is classified into three major types on the basis of clinical laboratory test results and genetic mutations, as delineated in Table 37-2.

Type 2 comprises at least four subtypes with variable inheritance patterns. Patients with type 2A vWD (≈15% of all with vWD) have decreased platelet-dependent functions owing to loss of high-molecular-weight multimers. Those with type 2B disease (≈5% of all with vWD) have vWF with increased affinity for platelet glycoprotein Ib (GP-Ib). Type 2M is less common and results in reduced binding of vWF to platelet GP-Ib despite the presence of large vWF multimers. Patients with type 2N disease have mutations that alter the vWF binding site for factor VIII. Impaired binding effects rapid clearance of factor VIII.¹⁰

If vWD is suspected, the initial screening tests are: (1) bleeding time, (2) closure time (vWF-dependent platelet function), (3) platelet count, and (4) aPTT. If results of these studies are positive or suspicious, more specific testing is pursued (Table 37-3).^9,13–15

Treatment decisions are based on severity of symptoms and type of vWD. Symptomatic patients should avoid nonsteroidal anti-inflammatory drugs. Desmopressin (DDAVP) is effective in patients with type I vWD perioperatively and in those with mild to moderate bleeding episodes. Patients with type 3 and severe forms of type 2A, 2B, and 2M disease usually require replacement therapy with vWF, factor VIII–vWF concentrates, or cryoprecipitate. In general, the goal of treatment in these patients is to maintain the activity of factor VIII and vWF between 50% and 100% for 3 to 10 days to address episodes of serious bleeding or for major surgery.¹¹

Giant Platelet Disorders

Giant platelet disorders are a group of rare disorders characterized by thrombocytopenia, large platelets, and variable bleeding symptoms. They are generally subcategorized into four groups: those with a structural defect (e.g., Bernard-Soulier syndrome with glycoprotein abnormalities), those with abnormal neutrophil inclusions (e.g., May-Hegglin anomaly), those with systemic manifestations (e.g., hereditary macrothrombocytopenia with hearing loss), and those with no specific abnormalities (e.g., Mediterranean macrothrombocytopenia).¹⁶

Bernard-Soulier syndrome, the most common of these platelet disorders, is characterized by thrombocytopenia, large platelets, and bleeding. It is attributed to dysfunction or absence of the GP-Ib/IX/V complex, which is a primary adhesion receptor of platelets.¹⁶ The disorder manifests early in life as bleeding symptoms, most frequently epistaxis or gingival or cutaneous bleeding. Frequently, a severe hemorrhagic episode is noted after surgery (e.g., circumcision). Laboratory findings include thrombocytopenia ranging from less than 30 to 200 × 10³/µL (normal) and a prolonged bleeding time with normal clot retraction.^16,17 Management of patients with this syndrome usually entails education and avoidance of minor trauma. In the event of significant hemorrhage, platelet transfusion is generally indicated.¹⁸

Glanzmann’s Thrombasthenia

Glanzmann’s thrombasthenia is an autosomal recessive disease with a large number of reported mutations. A defect in GP-IIb/IIIa renders platelets unable to aggregate.^19,20 Normal GP-IIb/IIIa allows platelets to bind soluble proteins and vWF. In Glanzmann’s thrombasthenia, platelets can attach to exposed endothelium but cannot form aggregates. A wide spectrum of phenotypic severity is reported, but mucocutaneous bleeding and absence of platelet aggregation are classic findings.²¹ Significant bleeding episodes typically require platelet transfusion.^16,19,22

Storage Pool Disorders

Storage pool disorders result from platelet granule deficiencies. The granules are usually divided into two groups: alpha granules (which contain vWF, thrombospondin, fibrinogen, and platelet-derived growth factor) and dense granules (which release adenosine diphosphate [ADP] and serotonin). Gray platelet syndrome is an example of an alpha-granule storage disorder.²³ This autosomal recessive disorder results in granules deficient in secretory proteins. Manifestations are typically limited to mucosal bleeding, but trauma-associated hemorrhage can occur. Laboratory analysis reveals moderate thrombocytopenia and a prolonged bleeding time. Preprocedural DDAVP and platelet transfusions form the basis for treatment.

Dense-granule deficiencies include Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome, and thrombocytopenia–absent radius syndrome.²⁴ Wiskott-Aldrich syndrome is an X chromosome–linked immunodeficiency manifested as thrombocytopenia with platelets of reduced size and function as well as eczema.²⁵ A defect in glycoprotein L115 (a leukocyte/platelet surface molecule) yields platelets that are unable to form aggregates.^25,26 Patients with the syndrome are typically diagnosed in early childhood with the constellation of thrombocytopenia, atopic dermatitis, and frequent infections. The only curative therapy is bone marrow transplantation. If platelet transfusion is required prior to transplantation, HLA-selected platelets should be used and all blood products should be irradiated.²⁶

Pathogenesis

The most common hemophilias are X-linked deficiencies of factor VIII (hemophilia A) and factor IX (hemophilia B).²⁷ Factor XI deficiency (hemophilia C) is a less common autosomally transmitted disorder. Factor VIII is a complex plasma glycoprotein produced by liver sinusoidal endothelial cells and by vascular endothelial cells.²⁸ It has a half-life of 12 hours in adults and is protected from premature degradation by vWF. Factor IX is a vitamin K–dependent protein synthesized by the liver with a plasma concentration approximately 50 times that of factor VIII and a half-life of 24 hours.²⁹ Bleeding in hemophilia results from a failure of secondary hemostasis. Although a normal platelet plug forms, stabilization of the plug by fibrin is defective owing to inadequate amounts of thrombin.

Diagnosis

Hemophilias A and B are clinically indistinguishable. A diagnosis of hemophilia is confirmed by an assay for the specific factor. However, factor VIII deficiency secondary to hemophilia A requires distinction from vWD by assays for vWF. Depending on the concentration of the factor, the bleeding tendency is classified as mild, moderate, or severe.³⁰ Mild disease has a factor VIIIc or IXc concentration between 0.05 and 0.40 IU/mL (5%-40% of normal) with bleeding manifestations after surgery, dental intervention, or trauma. Spontaneous bleeding is not seen. Moderate disease translates to a factor VIIIc or IXc concentration of 0.01 to 0.05 IU/mL (1% t-5% of normal). This concentration can result in bleeding into muscles and joints following minor injury. Major surgical or dental intervention effects severe hemorrhage.²⁹ Severe disease is seen with a concentration of factor VIIIc or IXc of less than 0.01 IU/mL (<1% of normal).

Though most cases of hemophilia are identified via family history, some appear as de novo mutations. Whereas severe disease is typically diagnosed by 2 years of age, mild or moderate disease may not be recognized until adulthood. The hallmark of severe hemophilia is spontaneous bleeding into joints and muscles.

Management

The primary goal of treatment is to sufficiently increase the concentration of the missing factor to stop or prevent spontaneous, traumatic, or surgical hemorrhage. A critical aim is to aggressively treat and prevent joint bleeding, which otherwise can lead to crippling arthropathy and joint deformity.³¹ Primary prophylaxis (prior to any episode of joint hemorrhage) to prevent this devastating complication is now recommended, with most centers recommending initiation prior to 3 years of age.

Although DDAVP can sufficiently raise factor VIII levels in patients with mild hemophilia A, factor concentrations are typically required for more significant disease. Multiple factor VIII and IX concentrations are available as either recombinant or plasma-derived products. For prophylaxis of a nonbleeding patient, a factor VIII concentration of 3% is considered adequate. A level of 30% is required for minor bleeding, and 50% for major bleeding. Prior to elective surgery, a factor VIII level greater than 80% is recommended, with a goal of 30% to 50% to be maintained in the first two postoperative weeks. The goals for hemophilia B include a factor IX level of 30% for minor bleeding and greater than 50% for major bleeding.³²

In some patients who undergo long-term replacement therapy, antibodies against factors VIII and IX develop. For these patients, recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrates might be necessary to achieve hemostasis. These agents act by bypassing the need for factors VIII and IX to achieve coagulation. The long-term goal for patients with high antibody titers is immune tolerance induction therapy, which results in a gradual reduction of antibody titers and increased tolerance of factor replacement therapy.

The most common precipitants of DIC are sepsis, extensive traumatic tissue injury, cancer, amniotic fluid embolism, and placental abruption. The final common pathway for all of these entities is systemic activation of the coagulation cascade. Proposed specific mechanisms are delineated in Table 37-4.^36–39

Even though DIC is a continuously progressing cascade of events, it can be described as three major clinical phases.⁴⁰ They are described here, and their typical laboratory findings are delineated in Table 37-5.

Fibrinolytic System

For an essential complete review of the fibrinolytic system, please refer to Chapter 34. In brief: Plasminogen circulates as an inactive zymogen. Activation of plasminogen by t-PA or urinary-type plasminogen activator (u-PA) results in its conversion to plasmin, a serine protease that degrades fibrin. Inhibitors of plasmin include plasminogen activator inhibitor (PAI-1; inhibits tissue and urinary-type plasminogen activators) and α2-antiplasmin (hepatic production). Thrombin-activatable fibrinolysis inhibitor (TAFI; a procarboxypeptidase activated by thombin-antithrombin complex [TAT]) also constrains fibrinolysis by cleaving the C-terminal lysine residue of fibrin fragments. This disruption prevents recruitment of plasminogen to a partially digested clot, thereby inhibiting fibrinolysis.

Pathogenesis

In this complex plasmin-plasminogen activator system, excessive bleeding can result from hyperactivity of plasminogen activators or deficient activity of fibrinolysis inhibitors. In primary fibrinolysis, there is pathologic direct activation of plasminogen. Excess circulating plasmin saturates plasminogen activator inhibitor-1 and α2-antiplasmin and cleaves fibrin and clotting factors, including factors V and VIII. Plasmin generated on the surfaces of platelets and endothelium inappropriately lyses hemostatic plugs. To counter the excess plasmin and fibrinolysis, excess thrombin is generated, resulting in microvascular thrombosis.

Etiology/Diagnosis

A primary hyperfibrinolytic state can develop in multiple clinical settings, including malignancy, liver failure, trauma, and congenital deficiency of fibrinolysis inhibitors.^41,42 Differentiating primary fibrinolysis from a secondary process such as DIC can be exceedingly difficult. The simplest laboratory findings to diagnose primary fibrinolysis are a short euglobulin lysis time in the absence of thrombocytopenia and the presence of schistocytes. Though challenging, the distinction between these two entities is critical as they require quite dissimilar treatments.

Management

The crux of treatment is inhibition of fibrinolysis using lysine analogues. The lysine analogues, aminocaproic acid and tranexamic acid, act as competitive inhibitors of the conversion of plasminogen to plasmin.⁴³ Often, factor replacement is also required, typically factors V and VIII. Prior to its removal from the market, aprotinin was also used as a therapy for this disorder.⁴⁴