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Disorders of Coagulation: Hemorrhage
Introduction
Understanding the complex biology of coagulopathy and hemorrhage is critical to the perioperative management of surgical patients. “Coagulopathy” is a term employed loosely in the literature and in the clinical setting. Coagulation is a physiologic defense mechanism aimed at maintaining the integrity of the circulatory system in the setting of vascular injury. There is a critical balance between coagulation and fibrinolysis aimed at preventing pathologic hemorrhage and thrombosis. Indicating “abnormal coagulation,” coagulopathy refers to both an excessive bleeding as well as thrombosis ; however, is most commonly used to refer to a tendency towards hemorrhage. It is applied both to patients with and without an identifiable coagulation abnormality on laboratory testing, which may be acquired or inherited.
Patients with vascular disease and those undergoing vascular surgery frequently pose complex hemostatic challenges – they are often elderly with cardiovascular comorbidities, may have uremia-related platelet dysfunction, are frequently on antiplatelet or anticoagulant therapy, and commonly require intraoperative anticoagulant therapy. Thus, the vascular surgeon is tasked with preventing adverse events by achieving adequate hemostasis without effecting extensive thrombosis. An understanding of normal and abnormal hemostasis is necessary to assimilate the pathophysiology of the coagulopathies and necessary treatments (see Ch. 38 , Normal Coagulation).
Diagnosis and Preoperative Screening for Bleeding Disorders
Identifying patients at risk for bleeding preoperatively allows the surgical team to initiate corrective treatment before performing a surgical procedure and to plan for optimal perioperative management. Evaluation for a possible bleeding diathesis starts with a screening based on history and physical examination, which help guide the appropriate laboratory evaluation. When the history and physical or initial laboratory evaluation is suggestive of a bleeding disorder, specialized medical or hematologic consultation should be considered for preoperative evaluation and optimization.
History and Physical Examination
A detailed history should elicit any previous episodes of bleeding with prior surgery, dental extractions, or trauma as well as any hematuria, melena, easy bruising or epistaxis. It is particularly important to inquire about previous hemostatic challenges such as surgery, trauma or childbirth since history may not be informative in the absence of a sufficient hemostatic challenge. Patient questionnaires and clinical risk assessment tools such as the International Society of Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH BAT) can assist in risk stratifying patients and guiding evaluation. , A patient with a family history of significant hemorrhagic complications should be evaluated for increased bleeding risk. Complete drug and medication histories (including homeopathic or herbal remedies) are important to evaluate for agents that affect platelet function or the clotting cascade. The physical examination should look for petechiae, excessive bruising as well as hepatosplenomegaly or spider naevi that may indicate liver disease, or joint effusions and other stigmata of previous bleeding.
Laboratory Testing
An abundance of laboratory tests are available for the evaluation of hemostasis. Therefore, one must adopt a systematic approach to selecting which, if any, laboratory studies a particular patient requires.
Risk-Stratified Approach to Laboratory Testing
In 1983, 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 ( Table 39.1 ), and the planned operation :
TABLE 39.1
Risk Stratified Approach to Preoperative Hemostatic Assessment
Adapted from Rapaport SI. Preoperative hemostatic evaluation: which tests, if any? Blood . 1983;61:229–231
| Risk level | Findings | Recommended testing |
|---|---|---|
| Level 1 | Negative history and physical examination for a proposed minor procedure | No further testing required |
| Level 2 | Negative history and physical examination for a proposed major procedure | aPTT, PT and platelet count |
| Level 3 | Suspicious history for major bleeding diathesis for a proposed major procedure | aPTT, PT, platelet count, and consider bleeding time or PFA-100 |
| Level 4 | Strongly suggestive history of a major hemostatic defect | aPTT, PT, platelet count, specific assays for factors VIII and IX, thrombin time, consider PFA-100 and consult with a hematologist |
Level I
Patients who have no bleeding history and will undergo minor procedures, such as lipoma excision. No further hematologic evaluation is required because the cost of testing outweighs the probability of finding an abnormality and the risk of bleeding and because testing that is not indicated may inappropriately delay surgery.
Level II
Patients who have no previous bleeding history but will undergo a major operation. This includes many patients undergoing open vascular operations that are potentially high risk for bleeding and involve intra- or postoperative anticoagulant or antiplatelet therapy that may increase bleeding risk. Normal prothrombin time, activated partial thromboplastin time (aPTT) and platelet count should effectively eliminate the risk of life-threatening bleeding.
Level III
Patients whose bleeding history raises concern for defective hemostasis and those in which the procedure may cause impaired hemostasis (e.g. use of high-dose heparin in cardiac procedures). In these patients, preoperative evaluation of the following factors is appropriate:
- 1.
Adequacy of hemostatic plug formation – platelet count and bleeding time
- 2.
Adequacy of coagulation reactions – prothrombin time (PT) and aPTT
- 3.
Size and stability of the fibrin clot – factor XIII levels and fibrinolysis screening particularly in patients with a history of delayed surgical bleeding
Level IV
A history or physical findings highly suggestive of abnormal hemostasis, and the surgical procedure is not a factor. In addition to performing the tests indicated for level III patients, the following should be considered (especially if the results of level III testing are normal):
- 1.
Factor VIII and factor IX levels
- 2.
Thrombin time (TT) – to detect dysfibrinogenemia
- 3.
Platelet function testing with the PFA-100 is useful to screen for vWD or impaired platelet function (preferred over bleeding time)
- 4.
Bleeding time after the administration of 600 mg of aspirin – to uncover von Willebrand Disease (vWD) or a qualitative platelet disorder.
Proper Blood Drawing
A properly drawn blood sample is paramount to interpreting the results of clotting tests; the specific methodology is beyond the scope of this chapter. 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). 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. The screening tests used to determine the cause of coagulopathy are summarized on Table 39.2 .
TABLE 39.2
Tests of Coagulation and Clinical Uses
| Test | Measured Variable | Causes of Abnormalities | Clinical Use |
|---|---|---|---|
| Prothrombin time (PT) | Factors II, V, VII, IX, and X; proteins C and S; tissue factor; fibrinogen | Consumptive coagulopathy, warfarin therapy, vitamin K deficiency, liver disease, deficiency of factors II, V, VII, IX, or X | Identify coagulopathy, monitor warfarin therapy |
| Activated partial thromboplastin time (aPTT) | All coagulation factors except factor VII and factor VIII | Consumptive coagulopathy, heparin therapy, lupus anticoagulants | Identify coagulopathy, monitor heparin therapy |
| Thrombin time (TT) | Fibrinogen (functional) | Consumptive coagulopathy, fibrinolysis, dysfibrinogenemia | Monitor fibrinolysis |
| Activated clotting time (ACT) | Global clotting function | Heparin use | Monitor intraoperative heparin therapy |
| Bleeding time (BT) | Platelet number and function | Abnormal platelet function, antiplatelet therapy, thrombocytopenia, uremia, von Willebrand Disease | Evaluate platelet function |
| Thromboelastography (TEG) | Clotting kinetics | Anticoagulants, platelet deficiency/dysfunction, fibrinolytics | Liver transplantation, monitoring during/after cardiopulmonary bypass |
| Fibrin degradation products (FDPs) | Fibrinolysis | Consumptive coagulopathy | Identify coagulopathy |
| Euglobulin lysis time (ELT) | Fibrinolysis | DIC, primary fibrinolysis | Monitor fibrinolysis, adjunct to diagnosing DIC or primary fibrinolysis |
DIC, disseminated intravascular coagulation.
Specific Laboratory Tests
Prothrombin time
PT is used to assess the extrinsic pathway of clotting (factor VII) as well as the common pathway (factors II, V, X and fibrinogen). The end point is the time required (in seconds) for a fibrin clot to form. Vitamin K antagonists such as warfarin prolong PT. Argatroban therapy and very high doses of heparin can also cause an elevated PT value secondary to thrombin (IIa) inhibition.
Activated partial thromboplastin time
The aPTT is used to assess the intrinsic pathway (factors VIII, IX, XI, and XII) and final common pathway (factors II, V, and X and fibrinogen) of clotting. Primary uses of aPTT include monitoring heparin therapy and detecting lupus anticoagulant, hemophilia A (factor VIII deficiency), and hemophilia B (factor IX deficiency). Table 39.3 lists the causes of prolongation of PT, aPTT, or both.
TABLE 39.3
Causes of Prolonged PT and aPTT
| Test Result | Cause of test result pattern | |
|---|---|---|
| Inherited Causes | Acquired Causes | |
| Prolonged PT and normal aPTT | Factor VII deficiency | Warfarin therapy Mild vitamin K deficiency Liver disease Disseminated intravascular coagulation |
| Prolonged aPTT and normal PT | Deficiency of factor VIII, IX or XI Deficiency of factor XII, prekallikrein or high molecular weight kininogen (not associated with bleeding) May be prolonged in von Willebrand Disease |
Anticoagulants including heparin, argatroban, bivalirudin, dabigatran Lupus anticoagulant (not associated with bleeding) Acquired inhibitor (autoantibody) against factor VIII, IX, XI, XII or vWF |
| Both PT and PTT prolonged | Deficiency of factor II (prothrombin, X, V or fibrinogen) Combined factor deficiency |
Severe vitamin K deficiency Disseminated intravascular coagulation Liver disease Acquired factor X deficiency in amyloidosis Acquired inhibitor of factor II (prothrombin), X, V or fibrinogen |
Thrombin time
TT measures the conversion of fibrinogen to fibrin, which is the final step in the clotting pathway. Prolongation of TT is attributable to direct thrombin inhibitor (DTI) therapy, heparin, lytic administration, disseminated intravascular coagulation, and dysfibrinogenemia.
Activated blood clotting time
The activated clotting time (ACT) test is performed by addition of a coagulant-accelerating matrix (e.g., diatomaceous earth) to a sample of whole blood and measurement of the time required for clot formation. This method is generally used to monitor adequacy of heparinization in the operating room or interventional suite.
Bleeding time
The bleeding time, or the time needed for a superficial wound to clot, is used to assess primary hemostasis. One measures bleeding time by making a controlled wound in the forearm or earlobe and subsequently measuring the time for clotting to occur. Clotting that takes longer than 5 minutes is considered abnormal. Bleeding time is mainly affected by the number and function of platelets, although vasoconstriction or vasodilatation may affect the bleeding time as well. Other factors that prolong the bleeding time include heparin therapy (as a result of platelet inhibition), vWD, thrombocytopenia, aspirin or other antiplatelet therapy, and uremia. The bleeding time was widely used in the past to predict surgical bleeding but has become less popular in recent practice since it is difficult to standardize and does not appear to predict the safety of surgical procedures.
PFA-100
The PFA-100 is a point of care assay to evaluate primary hemostasis. Citrated whole blood is exposed to high shear stress by aspirating it through cartridges that have an aperture within a membrane coated with either collagen and epinephrine (CEPI) or collagen and ADP (CADP). These agonists along with high shear stress induce closure of the aperture by a platelet plug. Closure time (CT) is measured, and prolongation of CT with one or both agonists is a sensitive screening test for aspirin effect, functional platelet defects or vWD. It is important to note that in addition to aspirin and nonsteroidal anti-inflammatory drugs, other medications such as common antidepressants may also affect PFA-100 closure times.
Thromboelastography and rotational thromboelastometry
Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are point of care tests which measure real-time clot characteristics, including formation and dissolution kinetics, as well as in situ fibrinolysis. Due to rapid turnaround time for these tests, they are useful for intraoperative monitoring of anticoagulation (e.g., cardiac surgery) as well as in goal-directed hemostatic therapy in a bleeding patient after trauma, surgery, or post-partum hemorrhage. There is emerging data to support the use of TEG/ROTEM to guide blood product administration in patients on extracorporeal membrane oxygenation (ECMO). Future studies may establish the utility of TEG/ROTEM for guiding anticoagulation on ECMO, especially in the pediatric population. ,
Fibrin degradation products
Fibrin degradation products (FDPs) occur as the result of primary or secondary fibrinolysis. Elevations of their levels are seen in disseminated intravascular coagulation (DIC), cirrhosis, eclampsia, and trauma, and following lytic therapy. The FDP assay has few specific clinical applications except in the attempt to identify primary fibrinolysis.
Euglobulin lysis time
The euglobulin lysis time (ELT) is an assay used to assess global function of the plasma fibrinolytic system. It measures the time required for a clot to lyse in a test tube (the normal value is 90–240 minutes). For this test to be useful, a patient must have adequate clot formation. This test is used as part of a panel to help differentiate a primary fibrinolytic state from DIC. A shortened ELT in patients without thrombocytopenia or schistocytosis is diagnostic of primary fibrinolysis, whereas a shortened ELT with thrombocytopenia or schistocytosis probably indicates DIC. ELT can also be used to determine the presence of excessive tissue plasminogen activator (t-PA) and deficiency of plasminogen activator inhibitor. A drawback of this assay is its significant reported interlaboratory variability.
Coagulopathies
Coagulopathy, or bleeding disorders, may be inherited or acquired and are classified as disorders of primary hemostasis or disorders of secondary hemostasis ( Table 39.4 )
TABLE 39.4
Types of Coagulopathy
| I. Disorders of Primary Hemostasis Commonly present with mucocutaneous bleeding such as epistaxis, petechiae, etc. Bleeding after trauma or invasive procedures. |
| Inherited | Acquired |
|---|---|
| Congenital platelet disorders including Glanzmann thrombasthenia, macrothrombocytopenias, storage pool defect von Willebrand Disease Connective tissue and vascular disorders (Ehlers–Danlos syndrome, Marfan syndrome, hereditary hemorrhagic telangiectasia, etc.) |
Acquired thrombocytopenia (immune thrombocytopenia, liver disease, drug-induced thrombocytopenia, hematological malignancy, etc.) Uremia Antiplatelet medications |
| II. Disorders of Secondary Hemostasis Commonly present with joint, soft tissue, or internal bleeding. Bleeding after trauma or invasive procedures. |
| Inherited | Acquired |
|---|---|
| Hemophilia A (factor VIII deficiency) Hemophilia B (factor IX deficiency) Rare inherited clotting disorders (deficiency of factor XI, X, VII, V, II and XIII) Congenital dysfibrinogenemia |
Acquired coagulation factor inhibitors Vitamin K deficiency Liver disease Anticoagulants Disseminated intravascular coagulation Amyloidosis associated coagulopathy Acidosis Dilution Hypocalcemia Hyperfibrinolysis |
Inherited Coagulopathies
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.
von Willebrand Disease (vWD) is the most common inherited bleeding disorder. Although it affects about 1% of the population, only 5% of those affected are symptomatic. Clinical manifestations range from none 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. , 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 39.5 . 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.
TABLE 39.5
Types of von Willebrand Disease
| Type | Transmission | Percentage of Cases of vWD (%) | Defect | Phenotype |
|---|---|---|---|---|
| 1 | AD | 75 | Quantitative deficiency of vWF | Mild–moderate bleeding |
| 2 | Autosomal but varied | 20% | Multiple qualitative defects (2A,2B, 2M, 2N) | Variable |
| 3 | AR | 5 | Absence/severe decrease in vWF | Severe bleeding |
AD, autosomal dominant; AR, autosomal recessive; vWD, von Willebrand Disease; vWF, von Willebrand factor.
If vWD is suspected, the initial screening tests are (1) bleeding time or PFA-100, (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, which includes vWf antigen levels, ristocetin cofactor activity (assessment of vWF function), vWF antigen:ristocetin cofactor activity ratio, factor VIII activity, and blood type (type O is associated with lower vWF levels). ,
Treatment decisions are based on severity of symptoms and type of vWD. Symptomatic patients should avoid NSAIDs. Desmopressin (DDAVP) is effective in patients with type 1 (and some type 2) 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.
Inherited Platelet Disorders
Inherited platelet disorders are rare conditions with varying degrees of phenotypic severity. These disorders affect multiple aspects of platelet function, namely aggregation, secretion, adhesion, and procoagulant activity. This group of disorders includes a large number of rare conditions, the most common of which are described in the following sections.
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., MYH9-associated disorders), those with systemic manifestations (e.g., hereditary macrothrombocytopenia with hearing loss), and those with no specific abnormalities (e.g., Mediterranean macrothrombocytopenia).
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. The disorder manifests early in life with bleeding, 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 × 10 3 /μL (normal) and a prolonged bleeding time with normal clot retraction. , Management of patients with this syndrome usually entails education and avoidance of minor trauma. In the event of significant hemorrhage, platelet transfusion is indicated.
Glanzmann Thrombasthenia
Glanzmann thrombasthenia is an autosomal recessive disease with a large number of reported mutations. A defect in GP-IIb/IIIa renders platelets unable to aggregate. , Normal GP-IIb/IIIa allows platelets to bind soluble proteins and vWF. In Glanzmann thrombasthenia, platelets can attach to exposed endothelium but cannot form aggregates. A wide spectrum of phenotypic severity is reported, but mucocutaneous bleeding and the absence of platelet aggregation are classic findings. Significant bleeding episodes typically require platelet transfusion. , , Recombinant factor VIIa (NovoSeven) is also used to control bleeding in patients with Glanzmann thrombasthenia and other severe platelet function disorders, and is particularly useful in patients who cannot receive platelet transfusions due to alloimmunization or antibody formation against the missing platelet glycoprotein.
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. 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. Wiskott–Aldrich syndrome is an X chromosome–linked immunodeficiency manifested as thrombocytopenia with platelets of reduced size and function as well as eczema. A defect in glycoprotein L115 (a leukocyte/platelet surface molecule) yields platelets that are unable to form aggregates. , 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.
Hemophilia
The hemophilias are inherited bleeding disorders caused by deficiencies of specific coagulation factors.
Pathogenesis
The most common hemophilias are X-linked deficiencies of factor VIII (hemophilia A) and factor IX (hemophilia B). Factor VIII is a complex plasma glycoprotein produced by liver sinusoidal endothelial cells and by vascular endothelial cells. 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. 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.
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