Key Clinical Questions
Introduction
In general, severe bleeding disorders are uncommon, unlike mild bleeding problems, which can be more challenging to diagnose. Most episodes of clinically significant bleeding requiring medical attention result from local causes (eg, a duodenal ulcer), surgery, or trauma. However, it is important to recognize when bleeding problems are more serious due to an underlying hemostatic abnormality.
Abnormal bleeding represents an important health care problem. For example, in the United States, it has been estimated that at least 5% to 10% of women of childbearing age seek medical care for menorrhagia and have bleeding severe enough to require medical intervention. Among the many defects that can cause abnormal bleeding, inherited and acquired von Willebrand disease (vWD) and platelet function disorders are much more common than defects in coagulation and fibrinolytic proteins.
Pathophysiology
Hemostasis consists of the following steps: (1) initiation and formation of the platelet plug, also known as primary hemostasis; (2) propagation and amplification of the clotting “cascade” or secondary hemostasis, which involves activation of a series of coagulation factors resulting in the generation of thrombin that cleaves fibrinogen to fibrin; (3) cross-linking of fibrin; (3) termination of procoagulant response by antithrombotic control mechanisms; (4) removal of the clot by fibrinolysis; and (5) tissue repair and regeneration.
When a vessel is injured, platelets adhere to exposed collagen and other components of the subendothelium as the first defense against bleeding. This initial adhesion is dependent on von Willebrand factor (vWF) as well as specific platelet receptors (eg, glycoprotein [GP] IbIXV) for vWF and collagen. This adhesion leads to platelet activation and shape change as well as platelet aggregation, which promotes recruitment of additional platelets.
Coagulation is initiated in vivo when endothelial or vascular cells are damaged. This results in exposure of blood to tissue factor (TF), which binds to factor VII (FVII) and its activated form, factor VII (FVIIa). TF-FVIIa complexes (extrinisic tenase) then activates factors IX and X directly. Activated factor IX can also form a complex with factor VIIIa as well as phospholipids and calcium, called the intrinsic tenase complex, that promotes further conversion of factor X to factor Xa. The generated factor Xa associates with activated factor V, phospholipids, and calcium to form the prothrombinase complex that activates prothrombin to thrombin. Intrinsic and extrinsic tenase are needed to generate enough thrombin for normal hemostasis. Once thrombin is generated, it cleaves fibrinogen to fibrin, which leads to formation of a fibrin clot and promotes platelet activation and the generation of activated factors V and VIII. Thrombin also results in the formation of activated XIII, an enzyme that crosslinks fibrin to make the clot more resistant to fibrinolysis (the cleavage of the fibrin clot).
When coagulation is activated, fibrinolysis is activated, leading to slow dissolution of the clot as part of wound healing. The process of fibrinolysis requires activation of plasminogen to plasmin, which is a serine protease that cleaves crosslinked fibrin. Fibrinolysis results in the formation of fibrinogen degradation products, including D-dimers. The generation of plasmin is controlled by both activators (ie, tissue-type and urinary-type plasmin activators) and inhibitors (ie, plasminogen activator inhibitor 1 and α2 plasmin inhibitor).
Bleeding disorders may be classified according to whether they are inherited or acquired, and by their underlying pathophysiology. The latter classification is often divided into the following broad categories: vascular disorders (eg, hemorrhagic telangiectasia and diseases of the connective tissue in the vessel wall, which are often challenging to diagnose); disorders of primary hemostasis (eg, platelet and vWF deficiencies and defects); disorders of secondary hemostasis (eg, clotting factor defects and deficiencies); and disorders of fibrinolysis (see Table 176-1). Some disorders (eg, severe vWD) impair hemostasis by impairing both platelet adhesion and fibrin formation, due to the associated factor VIII deficiency. Drugs that inhibit platelet function (eg, aspirin, nonsteroidal anti-inflammatory drugs, serotonin reuptake inhibitors) and those that inhibit coagulation (eg, heparin, warfarin) are important causes to consider when evaluating and managing an individual with bleeding.
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Does This Patient Have a Bleeding Disorder?
In general, a bleeding disorder should be suspected when bleeding occurs with minimal or no provocation, when it is more severe than expected for a given challenge, and when bleeding episodes occur repeatedly with challenges. Care should be taken to avoid asking very subjective questions about bleeding. For example, it is preferable to ask women about menstrual periods lasting longer than seven days, with more than two to three days of heavy flow, and/or periods that interfere with their lifestyle than to ask if they experience “heavy” periods. Similarly, asking about bruises as big as or larger than oranges and/or bruises appearing without provocation is better than asking about “easy bruising.”
While individuals with severe bleeding problems may report spontaneous bleeding and serious bleeding with major and minor hemostatic challenges, individuals with milder defects can report abnormal bleeding with some but not all significant hemostatic challenges. The clinical assessment should be directed toward identifying the type and severity of bleeding problems experienced by an individual, in order to plan appropriate laboratory testing and therapy.
The patient should be questioned about his or her current bleeding symptoms and past bleeding symptoms and a family history of bleeding problems (Table 176-2). The following characteristics of the bleeding should be determined: association with trauma or procedures and if it occurred with some or all minor and major procedures; site(s) (including joint bleeds); severity (eg, bleeding resulting in additional interventions such as blood transfusions, intensive care unit admission, and/or prolongation of hospitalization stay); duration of bleeding; and any treatments that were given to control bleeding (types of drugs or blood products). It may be helpful to determine if the patient received anticoagulants or drugs that inhibit platelet function. Female patients should be asked questions about menstrual periods and abnormal bleeding with childbirth and pregnancy losses. Mucocutaneous bleeding (ie, abnormal bruising, gum bleeding, and epistaxis) is more suggestive of a defect in primary hemostasis. Some bleeding symptoms, such as deep tissue bleeding, joint hemorrhages, and spontaneous unexplained hematuria are uncommon but can occur in severe inherited coagulation protein deficiencies. Some bleeding problems, such as epistaxis, can be experienced by individuals without bleeding disorders. Bleeding after trauma should be considered but can be difficult to evaluate because it is not specific to individuals with bleeding disorders.
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