Bleeding Disorders

Chapter 13 Bleeding Disorders



Allyson M. Reid, Thomas A. Brown, MD, Sonali J. Shah




Insider’s Guide to Bleeding Disorders for the USMLE Step 1


Bleeding disorders on the USMLE Step 1 are relatively straightforward if you understand the pathophysiology behind the diseases and correlate them with clinical findings. The best way to study for this section is to review the disorders mentioned in First Aid and be sure that you can reason through all the listed clinical findings and laboratory parameters. You should then attempt to go through these cases and create your own differential diagnosis before reviewing the answers. This will be great practice for the types of questions you will see and the thought processes that will be expected of you on boards.


In addition, pharmacology is especially important in this section. Many of the drugs that you are accountable for on boards and their associated mechanisms are listed for you in this chapter. Be sure to pay attention to pharmacologic antidotes whenever they are mentioned.



Basic concepts



1 Differentiate between the processes of primary and secondary hemostasis


Primary hemostasis involves the formation of a temporary platelet “plug” following binding of platelets to exposed collagen, platelet secretion of procoagulant substances (e.g., adenosine diphosphate [ADP], Ca2+), and platelet aggregation. This platelet plug is referred to as temporary because it is readily reversible at this stage. Secondary hemostasis involves the covalent cross-linking of fibrin between platelets, resulting in the formation of an irreversible platelet plug. This process is dependent on activation of the coagulation cascade (Table 13-1).


Table 13-1 Primary and Secondary Hemostasis























Feature Primary Hemostasis Secondary Hemostasis
Definition Temporary platelet plug Permanent platelet plug
Example disease(s) Von Willebrand disease Hemophilia A and B
Laboratory testing Bleeding time, platelet aggregation studies Prothrombin time (PT), partial thromboplastin time (PTT)
Clinical manifestations of disturbed mechanism Relatively mild (e.g., excessive bleeding after dental work or surgery), mucocutaneous petechiae Relatively severe (e.g., hemarthrosis)

Note: Disorders affecting platelet function will impair primary hemostasis, whereas disorders affecting the coagulation cascade will impair secondary hemostasis.



2 What molecule is responsible for the binding of platelets to collagen?


Von Willebrand factor (vWF), which is synthesized by vascular endothelium and attaches to both collagen and platelet receptors (specifically glycoprotein Ib [GPIb]), is responsible for the binding of platelets to collagen.



3 What constitutes the extrinsic, intrinsic, and common pathways in the coagulation cascade that forms the fibrin clot (secondary hemostasis)?


The extrinsic and intrinsic pathways are separate biochemical pathways that activate the coagulation cascade. Both the extrinsic and intrinsic pathways lead into the common pathway to cause formation of the fibrin clot.


The extrinsic pathway is referred to as “extrinsic” because the factor that activates it (tissue factor) is normally extrinsic to the vascular space and is exposed to the vascular space only when there is damage to the vascular endothelium that allows extracellular fluid and cells to enter. The extrinsic pathway includes tissue factor (factor III) and factor VII.


The intrinsic pathway has all of its constituents in the blood; hence, it is “intrinsic.” It is activated by exposure to negatively charged foreign substances. The intrinsic pathway includes factors XII, XI, IX, and VIII.


As mentioned, the common pathway is activated by either the extrinsic pathway or intrinsic pathway, and it eventuates in the formation of a fibrin clot. This pathway includes factors X, V, II, and I (Fig. 13-1).


image

Figure 13-1 Simplified coagulation cascade. HMWK, high-molecular-weight kininogen; PK, prekallikrein; PL, plasminogen; PT, prothrombin time; PTT, partial thromboplastin time; TF, tissue factor.


(From Ferri F: Ferri’s Best Test: A Practical Guide to Clinical Laboratory Medicine and Diagnostic Imaging. St. Louis, Mosby, 2004.)



4 What information can be provided by measuring the prothrombin time and activated partial thromboplastin time?


The prothrombin time (PT) reflects the time required for formation of a fibrin clot in a particular assay system (essentially, tissue factor is added to a sample of the patient’s plasma). Because the extrinsic pathway must activate the common pathway to form a fibrin clot, the PT really reflects the time it takes for the extrinsic pathway and the common pathway to form the clot. The PT can be prolonged by clotting factor deficiencies in either pathway.


The activated partial thromboplastin time (aPTT) also reflects the time required for formation of a fibrin clot in a particular assay system (in this case an activator of the intrinsic pathway is added to a sample of the patient’s plasma). In other words, this value measures the time it takes the intrinsic pathway and common pathway to form a clot. The aPTT can be prolonged by clotting factor deficiencies in either the intrinsic or common pathway.



5 What is the bleeding time? What is its clinical significance?


The bleeding time reflects the time required to form the platelet plug (primary hemostasis) and so reflects platelet function rather than functioning of the coagulation cascade. More commonly, however, in vitro platelet function tests are performed in place of measuring the bleeding time.



6 What is the mechanism of action of the following drugs? How do they affect the times just discussed?




A. Aspirin


Aspirin inhibits platelet function by irreversibly inhibiting the enzyme cyclooxygenase (COX), which normally functions to synthesize thromboxane A2. Thromboxane A2 normally functions to stimulate platelet aggregation and constriction of blood vessels, both of which act to limit bleeding following vessel trauma. Consequently, inhibition of thromboxane A2 by aspirin results in a prolonged bleeding time.


Note: Because aspirin is an irreversible inhibitor of platelet COX, its effect on platelet function lasts as long as the affected platelets remain in the circulation, ~ 7 days.



B. Heparin


Heparin stimulates the activity of antithrombin III (ATIII), which is a potent inhibitor of thrombin (factor II), as well as several other factors in the intrinsic pathway. Because of this preferential inhibition of the intrinsic pathway, heparin acts rapidly to prolong the aPTT but will do so only at higher doses. It has no effect on the bleeding time because it does not affect platelet function (except in cases of heparin-induced thrombocytopenia [HIT]).


Note: Excessive bleeding from heparin toxicity can be rapidly reversed by administering protamine sulfate.



C. Warfarin


Warfarin inhibits the production of vitamin K–dependent clotting factors in the liver (factors II, VII, IX, and X) by antagonizing the action of vitamin K. It preferentially prolongs the PT more than the aPTT. Because warfarin inhibits the synthesis of these clotting factors, and not their activity in the blood, there is a delay between its administration and its onset of action (typically a few days). For this reason, patients who require long-term anticoagulation are usually started on heparin and warfarin simultaneously, and once the patient is sufficiently well anticoagulated with warfarin, the heparin can be discontinued and the prothrombin time maintained within a therapeutic range.


Note: The effects of warfarin can be reversed by administering vitamin K, and this takes about a day or two. For emergent surgical procedures, fresh frozen plasma can be given to immediately replace the deficient clotting factors. Warfarin also inhibits the production of protein C and protein S, both vitamin K–dependent proteins secreted by the liver that exert anticoagulant effects. Consequently, inhibition of protein C and protein S synthesis by warfarin can initially result in a hypercoagulable state (in which the patient is prone to clotting). For this reason, “loading” doses of warfarin are not recommended. Instead, warfarin should be administered with heparin during the first week of therapy.



7 What is the mechanism of action of tissue plasminogen activator?


As its name suggests, tissue plasminogen activator (tPA) is an enzyme that activates the plasma enzyme plasminogen by converting it into its active form, plasmin. Plasmin is an enzyme that proteolytically cleaves fibrin strands, thereby degrading fibrin clots that may obstruct vessels. In addition to tPA, streptokinase and urokinase are sometimes referred to as “clot busters” (Table 13-2).



Table 13-2 Pharmacotherapy for Hemostasis

image


Summary Box: Hemostasis, Coagulation Cascade, Pharmacotherapy




image Primary hemostasis is the process whereby platelets adhere to the underlying collagen of damaged vascular endothelium and form a temporary platelet “plug.”


image Secondary hemostasis is the process whereby these platelets are covalently cross-linked to form an irreversible platelet plug, a process that requires clotting factors.


image Disorders affecting platelet function will impair primary hemostasis. Platelet function can be tested by checking bleeding time (rarely done) or in vitro platelet function tests (more commonly done).


image Both the extrinsic and intrinsic pathways lead into the common pathway to cause formation of the fibrin clot.


image The prothrombin time (PT) reflects the time it takes for the extrinsic and common pathways to form a fibrin clot. The PT can be prolonged by clotting factor deficiencies in either pathway.


image The activated partial thromboplastin time (aPTT) reflects the time it takes for the intrinsic and common pathways to form a fibrin clot. The aPTT can be prolonged by clotting factor deficiencies in either pathway.


image Aspirin irreversibly inhibits platelets by inhibiting cyclooxygenase (COX), preventing the formation of thromboxane A2, which normally promotes platelet aggregation and vasoconstriction in response to endothelial damage. Aspirin therapy results in a prolonged bleeding time.


image Heparin stimulates antithrombin III activity, thereby inhibiting the intrinsic pathway and prolonging the aPTT. Heparin has no effect on bleeding time because it does not (typically) affect platelet function. Heparin toxicity can be reversed with protamine sulfate.


image Warfarin (Coumadin) inhibits the synthesis of vitamin K–dependent clotting factors (II, VII, IX, and X) by antagonizing the action of vitamin K. It preferentially prolongs the PT. There is typically a delay of several days before patients achieve a therapeutic international normalized ratio (INR) on warfarin because warfarin inhibits the synthesis of further clotting factors but does not inhibit the activity of existing plasma clotting factors.


image Warfarin toxicity can be reversed by administering vitamin K (takes 1-2 days) or fresh frozen plasma (rapid).


image Tissue plasminogen activator (tPA), streptokinase, and urokinase are “clot-busting” drugs that can be used in particular clinical scenarios such as ST-segment elevation myocardial infarction or acute ischemic cerebrovascular accident.




Case 13-1


A 7-year-old boy is brought to your office by his mother because of a swollen right knee. When questioned, she states that this has happened in the absence of significant trauma several times over the past few years. He does not appear febrile, and a complete blood count (CBC) is normal. Both parents are healthy, although the mother says that her father (the boy’s maternal grandfather) had “some type of bleeding disorder.”



1 What is the most likely diagnosis?


Hemophilia typically presents with spontaneous bleeding into joints (hemarthrosis) and soft tissues or prolonged bleeding following dental procedures or minor surgery. Because hemophilia A is more common than hemophilia B, this boy most likely has hemophilia A.



2 What is the cause of this disorder and how is it inherited?


Hemophilia A is caused by a hereditary deficiency of factor VIII and is inherited in an X-linked recessive manner. Females are very rarely affected because the approximate 50% factor levels in most carriers are sufficient to prevent excessive bleeding. In rare circumstances, females may be affected due to unequal inactivation (lyonization) of factor VIII or factor IX alleles (see Chapter 11, Genetic and Metabolic Disease, for more information).


In this case study, in which the maternal grandfather was affected, the boy’s mother is an asymptomatic female carrier who transmitted the “bad” X chromosome (from her father) to the child.


Note: Hemophilia B is an X-linked recessive disease in which factor IX of the coagulation cascade is deficient.

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Apr 7, 2017 | Posted by in NURSING | Comments Off on Bleeding Disorders

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