Jahan Mohebali, MD
Ms. Smith is a 52-year-old female who presents to your office for a possible laparoscopic sigmoid colectomy. She states that she has no significant medical history other than diverticulitis. Her only previous surgery was a wisdom tooth extraction at the age of 21. She notes that the procedure was uneventful; however, she continued to have significant oozing from her gums for approximately 24 hours. On review of systems, she notes that she has always bruised quite easily as long as she can remember. Further questioning reveals that she may have also had menorrhagia, although this was never formally diagnosed. Her laboratory data reveal a normal complete blood count. Her coagulation panel is notable for a mildly elevated partial thromboplastin time (PTT) and a prolonged bleeding time.
1. What is the single best predictor of an inherited disorder of coagulation?
2. What are the two major categories of coagulation abnormalities and what symptoms are associated with each?
3. What is the standard workup when an inherited coagulopathy is suspected?
4. Which laboratory tests will distinguish a platelet disorder from a problem with coagulation factors?
In order to understand congenital coagulation disorders, one must begin by briefly reviewing the steps of normal hemostasis (see Figure 59-1). Although it is not essential to memorize every step of the cascade, one must understand that there is an intrinsic pathway that is initiated by exposure of blood to collagen as may happen with endothelial damage and an extrinsic pathway that is initiated with exposure to tissue factor. These pathways converge with the activation of factor X and formation of the tenase complex, which initiates the final common pathway by converting prothrombin to thrombin, and finally fibrinogen to fibrin. It is also important to note that platelets not only are involved in forming the initial hemostatic plug but also serve as the surface on which the tenase complex assembles.
Figure 59-1. Coagulation cascade and laboratory assessment of clotting factor deficiency. (Reproduced, with permission, from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill Education; 2012. Figure 116.1. <www.accessmedicine.com>. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)
1. The single best predictor is the preoperative history and physical exam. Careful history taking is usually more revealing than preoperative coagulation studies.
The preoperative hematologic history should focus on whether or not the patient has ever experienced a previous episode of abnormal bleeding. If the patient has had a previous operation, he or she should be questioned regarding any complications related to bleeding or poor hemostasis intraoperatively or in the postoperative period. If the patient has not undergone a previous surgical procedure, the history should focus on prolonged or abnormal bleeding related to trauma, previous episodes of mucosal bleeding or epistaxis, a history of menorrhagia in women, extensive bleeding after dental procedures, or a history of subcutaneous, intramuscular, or intra-articular hemorrhage.
2. Most congenital coagulopathies are the result of an abnormality related to platelets, to coagulation factors, or, occasionally, to both. Whenever a disorder of hemostasis is suspected, an attempt should be made to determine which of these is the culprit. Bleeding related to thrombocytopenia or decreased platelet function is typically manifested as mucosal bleeding, epistaxis, prolonged bleeding after tooth extraction, and menorrhagia (in women). Bleeding as a result of coagulation factor abnormalities is more likely to present as major subcutaneous, intramuscular, and, classically, intra-articular hemorrhage following minor trauma (see Table 59-1).
Table 59-1. Comparison of Signs Associated With Each Type of Coagulation Disorder
The most commonly encountered inherited coagulopathy is von Willebrand disease (vWD). This disorder should be thought of as a functional platelet disorder. The prevalence of vWD has been reported to be as high as 1 in 100 in some populations. The second and third most commonly encountered hereditary coagulopathies are factor VIII deficiency resulting in hemophilia A with a prevalence of roughly 1 in 10,000 and factor IX deficiency resulting in hemophilia B with a prevalence of roughly 1 in 100,000.
von Willebrand factor (vWF) is a multimeric protein contained within vascular endothelial cells and in plasma that facilitates the binding of platelets to subendothelial collagen through Gp1b receptors. It also serves as a stabilizer of factor VIII, which is why patients with vWD may also have some degree of factor VIII deficiency. As previously mentioned, because vWD is a functional platelet disorder, these patients will typically have a history of mucosal bleeding, significant bleeding after dental procedures, epistaxis, and menorrhagia (in women). In fact, patients with the most severe form (type 3) may actually suffer from hemarthroses because of their factor VIII deficiency.
Other less common congenital platelet disorders may include thrombocytopenia from splenic sequestration as a result of a multitude of congenital storage and hematopoietic disorders, and other functional platelet disorders. Glanzmann thrombasthenia and Bernard-Soulier syndrome are two other inherited functional platelet disorders that result in bleeding despite a normal platelet count (see Figure 59-2).
Figure 59-2. Platelet adhesion and aggregation. GpIb receptors allow platelets to bind to the collagen in the subendothelium with the help of vWF. These are the receptors affected in Bernard-Soulier syndrome. GpIIa/IIIb receptors allow platelets to bind to one another with the help of fibrinogen and are decreased in Glanzmann thrombasthenia.
Coagulation factor deficiencies
Hemophilia A and hemophilia B resulting from factor VIII and factor IX deficiency, respectively, are considered to be the second and third most common hereditary bleeding diatheses. Both diseases are inherited on the X chromosome and because they are coagulation factor abnormalities, patients will typically present with subcutaneous, intramuscular, or intra-articular hemorrhage following minor trauma. The degree of bleeding depends on the level of factor present in plasma. It is important to remember that factor VIII is the only coagulation factor that is not synthesized in the liver. Mild deficiencies in factor VIII can be treated with cryoprecipitate that contains high concentrations of the factor, or with desmopressin (DDAVP) that increases release of vWF and factor VIII from the endothelium. In most cases, however, deficiencies in factor VIII or IX are treated with the administration of factor concentrates. In general, factor levels need to be maintained at a minimum of 50% of normal in the intraoperative and postoperative periods until wound healing is complete in order to prevent complications related to hemorrhage. Other congenital factor deficiencies exist, but these are exceedingly rare and beyond the scope of this chapter.
3. When a congenital coagulopathy is suspected, workup should proceed as follows:
A. Step 1—History and physical exam. Begin with a full history and physical exam focusing on any bleeding complications associated with previous operations, or a history of abnormal bleeding. It is important to remember that acquired causes of coagulopathy are more prevalent than congenital causes and the history and physical exam should be used to look for these diseases as well.
B. Step 2—Obtain a medication list. A full list of antiplatelet and antithrombotic medications taken by the patient should be obtained, and the patient should be asked about other medications that may interfere with platelet function such as aspirin, NSAIDs, fish oil, or H2 blockers.
C. Step 3—Screen for acquired causes of coagulopathy such as organ dysfunction. Liver disease may result in a coagulopathy as a result of poor synthetic function, and uremia secondary to renal failure results in abnormal platelet function by interfering with the action of both GpIIb/IIIa and GpIb receptors. The physical exam should not only look for evidence of abnormal hemostasis and hematopoiesis such as petechiae, hematomas, lymphadenopathy, and splenomegaly but also screen for stigmata of advanced liver and renal disease.
D. Step 4—If indicated, obtain appropriate laboratory studies. If there is ongoing concern for a bleeding diathesis, a complete blood count and prothrombin time (PT), international normalized ratio (INR), and PTT should be obtained. If there is concern for a platelet disorder despite a normal platelet count, a bleeding time assay and ristocetin cofactor assay should be obtained.
4. In order to interpret laboratory data in the workup of congenital coagulopathies, one must understand which tests are representative of each part of the normal hemostasis pathway (see Figure 59-2).
Laboratory evaluation of platelet disorders
Platelet disorders can be evaluated with a complete blood count and bleeding time. If the complete blood count does not demonstrate thrombocytopenia and there is ongoing concern for a platelet disorder, a bleeding time assay can be obtained. To determine the bleeding time, a 9 mm long × 1 mm deep incision is made on the forearm and a blood pressure cuff is inflated to 40 mm Hg to create back pressure. Blood is blotted away every 30 seconds from the incision until bleeding stops. Although this test is extremely sensitive for picking up functional platelet disorders, it is quite difficult to standardize and is therefore not commonly used.
If there is suspicion for vWD, a ristocetin cofactor assay can be obtained. When added to normal blood, ristocetin will cause vWF to bind the GpIb receptor on platelets. In vWD, addition of ristocetin will not result in platelet clumping. It should be reiterated that vWD will result in a factor VIII deficiency and, therefore, some degree of PTT prolongation.
Table 59-2 shows the most common lab abnormalities associated with each of the above-mentioned bleeding diatheses.
Table 59-2. Common Lab Abnormalities Associated With Bleeding Diatheses
Laboratory evaluation of factor deficiencies
PT: In general, the PT will be prolonged when there are low levels of factors in the extrinsic pathway and everything downstream of it, that is, VII, X, and V, prothrombin, and fibrinogen. The INR is a standardized measurement of the PT and is used to monitor anticoagulation therapy.
PTT: The PTT is representative of the function of the intrinsic pathway and everything downstream of it, that is, factors VIII, IX, XI, XII, X, V, prothrombin, and fibrinogen. Therefore, hemophilia A and B are associated with a prolonged PTT.
Clearly, both the PT and PTT are affected by factors in the final common pathway and therefore any abnormality of the tenase complex and downstream of it will result in an elevation of both the PT and PTT.
A prolonged PT in the setting of a normal PTT ensures that the abnormality lies within the extrinsic pathway, upstream of the final common pathway. Only factor VII deficiency can cause this pattern of lab values.
Likewise, a prolonged PTT, but normal PT, implies that the abnormality lies within the intrinsic pathway, upstream of the final common pathway. This pattern will be seen with deficiency of factor VIII, IX, XI, or XII.
TIPS TO REMEMBER
The best screening test for a congenital coagulopathy is the preoperative history and physical exam.
Bleeding disorders may be a result of abnormalities of platelets, coagulation factors, or both.
Platelet disorders typically present with mucosal bleeding, epistaxis, prolonged bleeding after tooth extraction, and occasionally menorrhagia (in women).
Coagulation factor disorders typically present with more severe bleeding such as intramuscular and intra-articular hemorrhage.
A prolonged PT with a normal PTT suggests a problem in the extrinsic pathway (ie, factor VII deficiency). A prolonged PTT with a normal PT suggests a problem in the intrinsic pathway. If both the PT and PTT are prolonged, the problem must affect the final common pathway.
Bleeding time is prolonged in functional platelet disorders, but the test is not used very often because of difficulty in its standardization.
The three most common congenital coagulopathies are vWD (~1 in 100), hemophilia A (~1 in 10,000), and hemophilia B (1 in 100,000).
1. A 25-year-old male presents to your clinic for preoperative evaluation prior to repair of a right inguinal hernia. Your history and physical exam reveals a previous history of two episodes of intra-articular hemorrhage. If the patient has a congenital coagulopathy, he may have any one of the following diseases except which one?
A. Hemophilia A
B. Hemophilia B
C. Splenic sequestration
2. What is the most important step in screening for the presence of a congenital coagulopathy?
A. Obtaining a complete blood count
B. Checking PT, INR, and PTT
C. Obtaining a ristocetin cofactor assay
D. Performing a thorough history and physical exam
3. Administration of desmopressin (DDAVP) will help to correct all of the following congenital coagulopathies to some degree except which one?
B. Hemophilia A
C. Hemophilia B
4. A preoperative history reveals previous episodes of epistaxis and prolonged bleeding after wisdom tooth extraction. The patient is likely to have any of the following congenital coagulopathies except which one?
A. Bernard-Soulier syndrome
B. Factor VII deficiency
C. Glanzmann thrombasthenia
1. C. A history of intra-articular hemorrhage suggests a problem with the coagulation cascade. This means either hemophilia A or B. Splenic sequestration, on the other hand, is a platelet disorder and rarely results in intra-articular hemorrhage.
2. D. A thorough history and physical exam should be used for screening in order to avoid unnecessary testing.
3. C. Desmopressin or DDAVP administration results in release of factor VIII and vWF from the endothelium (remember that factor VIII is the only factor that is not produced in the liver). Factor IX is synthesized in the liver and, therefore, DDAVP will have no efficacy in hemophilia B.
4. B. The symptoms described suggest a platelet disorder such as A, C, or D.