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CHAPTER 172 Approach to Patients with Bleeding

Disorders

Kathryn Webert, MD, MSc, FRCPC

Catherine P. M. Hayward, MD, PhD

Key Clinical Questions

When should a bleeding disorder be suspected? How should patients suspected of bleeding disorders be evaluated? How does one interpret the results of hemostasis testing? What is the general approach to management of an individual with a bleeding disorder?

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

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trauma. However, it is important to recognize when bleeding problems are more serious or more frequent 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 REVIEW OF NORMAL HEMOSTASIS

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; (4) termination of procoagulant response by antithrombotic control mechanisms; (5) removal of the clot by fibrinolysis; and (6) 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 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 (extrinsic 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, which 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 cross-links 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 cross-linked fibrin. Fibrinolysis results in the formation of fibrin 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).

GENERAL CLASSIFICATION OF BLEEDING DISORDERS ACCORDING TO PATHOPHYSIOLOGY

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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 172-1). 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.

TABLE 172-1 Questions to Consider when Evaluating a Patient for a Possible Bleeding Disorder

What are the patient’s bleeding symptoms? • Is there a personal or family history of bleeding with trauma or procedures? • What are the site(s) of bleeding? • For women: Is there a history of prolonged, heavy periods or bleeding with childbirth? • What is the severity of bleeding? • What is the duration of bleeding events? • Has the patient required any treatments for bleeding? Does the history suggest a congenital or acquired problem? • Note: For congenital bleeding disorders, the bleeding symptoms may date back to

childhood and may affect other family members; acquired bleeding disorders should be considered when the bleeding problems are more recent, and a drug-induced defect should be excluded.

What is the timing of the bleeding? • Is the bleeding immediate or delayed (onset one or more days after challenges)? Is the bleeding systemic or local? • Note: Local bleeding is suggestive of a local cause, although acquired or inherited

bleeding disorders can make it worse. Are there any aggravating or contributing factors? • Note: The drug history (prescription, nonprescription, and other supplements) should be

carefully reviewed. What is the patient’s general medical history? • Does the patient have a history of liver, kidney, or thyroid diseases? The patient should

also be questioned about relevant symptoms of these disorders. • Does the patient have a history of pregnancy loss (may be associated with disorders of

fibrinogen). • Does the patient have a history of poor wound healing (can occur in a variety of

bleeding disorders).

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How many times has the patient experienced a significant hemostatic challenge, and how many of these were associated with abnormal bleeding? • Note: A history of bleeding with only some challenges suggests a mild or acquired

bleeding problem.

DOES THIS PATIENT HAVE A BLEEDING DISORDER? WHEN TO SUSPECT 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 7 days, with more than 2 to 3 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. While inherited, severe bleeding problems typically present early in life, milder inherited bleeding problems and acquired bleeding problems often get diagnosed in adult life. 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.

KEY COMPONENTS OF THE HISTORY

What are the patient’s bleeding symptoms?

The patient should be questioned about his or her current bleeding symptoms and past bleeding symptoms and a family history of bleeding problems (Table 172-2). 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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TABLE 172-2 General Classification of Bleeding Disorders According to Pathophysiology

Vascular disorders • Congenital (eg, hereditary hemorrhagic telangiectasis, Ehlers-Danlos syndrome) • Acquired (eg, secondary to steroid use, vitamin C deficiency) Disorders of platelets and their function • Thrombocytopenia

Acquired (eg, drug-induced, immune-mediated) Congenital (eg, inherited platelet or bone marrow disorders)

• Disorders of platelet function Congenital (secretion defects are the most common) Acquired (eg, drug-induced, renal failure)

• von Willebrand disease Congenital Acquired

Disorders of coagulation • Coagulation factor deficiencies

Congenital (ie, hemophilia A [factor VIII deficiency], hemophilia B [factor IX deficiency], deficiencies or defects of factors II, V, VII, X, XI, fibrinogen, or XIII)

Acquired (vitamin K deficiency, liver disease, anticoagulant therapy, massive blood loss [hemodilution], acquired coagulation factor inhibitors)

Disorders of fibrinolysis • Congenital (ie, α-2 antiplasmin deficiency, plasminogen activator inhibitor-1 deficiency,

Quebec platelet disorder) • Acquired (ie, hyperfibrinolytic syndrome, disseminated intravascular coagulation) Other • Acquired bleeding secondary to other disorders such as renal failure, thyroid disease, or

Cushing syndrome

PRACTICE POINT

The timing of the bleeding relative to the surgical or dental procedure may be an important clue to the etiology of the bleeding disorder. Patients with disorders of primary hemostasis will often describe abnormal bleeding during or within a few hours whereas disorders of secondary hemostasis (including defects in clot stabilization and fibrinolysis) typically manifest as delayed-onset bleeding evident days following trauma or surgery.

What is the timing of bleeding?

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The bleeding history is often used to assess when abnormal bleeding occurred (eg, same day or days later) relative to invasive surgical or dental procedures. Bleeding during, immediately after, or on the same day as the challenge is suggestive of a disorder of primary hemostasis (see Disorders of Primary Hemostasis later in this chapter), whereas bleeding that becomes problematic one or more days after a challenge is more typical of a factor deficiency or a fibrinolytic defect.

Is the bleeding disorder congenital or acquired, and are there aggravating or contributing factors?

Inherited problems tend to present earlier in life than acquired problems unless they are mild. Inherited problems are often associated with a positive family history, which may be negative if the condition is recessive or X-linked. A thorough bleeding history should include questions about potential aggravating or contributing factors such as new medications (eg, aspirin or antidepressant therapy).

Individuals with acquired bleeding disorders often describe bleeding that is more recent in onset. Causes of an acquired bleeding disorder are listed in Table 172-2 and include liver disease, vitamin K deficiency, autoimmune-mediated conditions (eg, immune thrombocytopenic purpura), hypothyroidism, acquired factor VIII deficiency or acquired VWD, and other conditions such as Cushing syndrome.

It is important to emphasize that the patient’s entire bleeding history must be assessed in order to determine if the problem is mild or severe and if it is likely congenital or acquired.

Has the patient experienced any hemostatic challenges?

Patients should be questioned about how many operative and invasive dental procedures they have undergone, and how many of these were associated with abnormal bleeding. It may be helpful to ask if the patient has experienced any unusually large ecchymosis around incisions when evaluating the surgical bleeding history. It is important to note that individuals who have undergone a number of common surgical and dental procedures (eg, tonsillectomy, wisdom tooth extraction) without experiencing abnormal bleeding might still have a mild bleeding problem (particularly if other aspects of their bleeding history are abnormal); however, they are unlikely to have a severe bleeding disorder. Alternately, it is important to recognize that sometimes abnormal bleeding occurs in healthy individuals undergoing a major procedure due to technical complications.

What is the patient’s general medical history? Is there a systemic disease that is causing or contributing to the patient’s bleeding symptoms?

An evaluation of a patient’s general medical history for new or worsening bleeding, and other changes in health, is important for assessing undiagnosed liver, kidney, or endocrine disorders such as thyroid disease or Cushing syndrome. The manifestations of some bleeding disorders, such as severe fibrinogen deficiency, can include recurrent pregnancy losses (due to hemorrhagic abruptions) and poor wound healing. Intracranial hemorrhage is seen more frequently in severe bleeding disorders (such as severe congenital factor XIII deficiency, severe coagulation factor, or fibrinolytic protein deficiencies and/or defects). Anemia can make bleeding worse and a history of iron deficiency (with or without anemia) can suggest chronically increased blood loss (eg, due to menorrhagia). Sometimes the

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history can suggest a rare inherited syndrome such as a platelet disorder associated with albinism, hearing loss, renal insufficiency, or skeletal malformations.

Has the patient ingested any medications that may have caused or worsened bleeding?

It is helpful to obtain a list of all medications (including prescription, nonprescription, and herbal) that the patient was taking in order to determine what might have caused or worsened their bleeding. Drugs can cause or worsen bleeding by a variety of mechanisms inducing: thrombocytopenia (eg, quinine, penicillin); impaired platelet function (eg, due to nonsteroidal anti-inflammatory drugs such as aspirin, clopidogrel, serotonin reuptake inhibitors, or fish oil supplements); or defective coagulation (eg, due to heparin or warfarin).

PHYSICAL EXAMINATION

The physical examination is often not very informative in individuals with a bleeding disorder. An initial assessment of acute bleeding should determine the patient’s hemodynamic status and if there are signs of anemia. Blood blisters in the mouth, hemorrhages on the bite margins in the mouth, and petechiae (tiny red-colored skin lesions that reflect small hemorrhages into the skin, particularly on dependent parts of the body and at sites of trauma) may suggest significant thrombocytopenia. Large bruises or purpura may suggest a defect in primary hemostasis or acquired hemophilia. Sometimes the purpuric skin lesions of severe anticoagulant protein deficiencies (eg, purpura fulminans due to severe congenital protein C deficiency) are mistaken for skin bleeding. Abnormalities in joints, lymph nodes, spleen, and liver should raise concern for the possibility of a secondary bleeding disorder.

DIFFERENTIAL DIAGNOSIS BASED ON CLINICAL ASSESSMENT

Table 172-3 outlines the differences between disorders of primary and secondary hemostasis.

TABLE 172-3 Distinction between Disorders of Primary and Secondary Hemostasis

Disorders of Primary Hemostasis

Disorders of Secondary Hemostasis

Timing of bleeding Immediate Delayed (starts one or more days after trauma or surgery)

Petechiae Common (especially with thrombocytopenia)

Not seen

Ecchymoses Common May occur (usually large) Deep hematomas Not common Common in severe factor

deficiencies Joint bleeding (hemarthoses) Not common Common in severe factor

deficiencies Mucous membrane bleeding Common Uncommon

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Epistaxis Common, particularly in childhood

Uncommon

Menorrhagia Common May occur Inheritance (if congenital) Dominant or recessive Most common cause

(hemophilia) is X-linked

Disorders of primary hemostasis

Patients with disorders of primary hemostasis will often describe experiencing abnormal bleeding during or within a few hours of a surgical or dental procedure. These problems, with or without mucocutaneous bleeding symptoms, should raise questions about VWF and platelet abnormalities (both qualitative and quantitative) or, less commonly, blood vessel abnormalities. Defects in primary hemostasis can also present as troublesome epistaxis and/or gingival bleeding, petechiae, superficial bruising or ecchymosis, and menorrhagia. Petechiae are very suggestive of a platelet or vascular disorder.

Disorders of secondary hemostasis

Disorders of secondary hemostasis typically manifest as delayed-onset bleeding that becomes evident in the days following trauma or surgical procedure. When there is a severe factor deficiency, there can be spontaneous bleeding into joint spaces (hemarthroses) and into deep, soft tissues (eg, muscle hematomas). The most common inherited disorders of secondary hemostasis include hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency). Acquired hemophilia, due to an antibody directed against factor VIII, accounts for about 10% of all hemophilia. Factor XIII deficiency and fibrinolytic disorders can also present with delayed bleeding, but these conditions are less common. Acquired autoantibodies against coagulation proteins are important but infrequent causes of bleeding and most commonly affect factor VIII, VWF, factor XIII or factor V.

HOW SHOULD THIS PATIENT WITH A SUSPECTED BLEEDING DISORDER BE INVESTIGATED?

Investigations for bleeding problems need to consider the etiologies of mild and severe and common and rare disorders. Figure 172-1 summarizes a stepwise approach to investigation, some of which may be performed at the time of a specialist evaluation. Often, a broad range of tests is needed to assess an individual with a suspected bleeding disorder (see Figure 172-1). A complete blood count is helpful to evaluate for thrombocytopenia and to determine if there are other hematologic abnormalities such as anemia (which may reflect acute or chronic bleeding), or white blood cell abnormalities that may suggest an underlying bone marrow disorder. An assessment for iron deficiency (which may be present without anemia) should be considered. A blood group and antibody screen should be done before surgery in individuals with a history of abnormal bleeding and can be helpful when interpreting VWD testing results.

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Figure 172-1 A staged assessment to the diagnostic testing of bleeding disorders. (APTT, activated partial thromboplastin time; CBC, complete blood count; INR, international normalized ratio; TCT, thrombin clot time; VWF, von Willebrand factor.)

When selecting tests of hemostasis to investigate a bleeding problem, it is helpful to consider that coagulation defects are generally much rarer than defects in platelets and VWF. Like the bleeding time, closure times measured by the platelet function analyzer

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(PFA)-100 are optional and cannot be used to exclude VWD or platelet disorders. While it is common practice to order a prothrombin time (PT, sometimes reported as an international normalized ratio [INR]) and an activated partial thromboplastin time (APTT) in individuals with bleeding problems, the results are often normal. A fibrinogen level and a thrombin time should be considered because the PT and APTT are insensitive to fibrinogen problems. Table 172-4 lists the different causes of abnormal coagulation tests.

TABLE 172-4 Differential Diagnosis of Coagulation Test Abnormalities

PT APTT Thrombin Time Fibrinogen Platelet Count

Reference Intervals ~ 10- 13 s

Ranges Vary

150-400 mg/dL 1.5-4.0 g/L

150-400 × 106/mL

Fibrinogen deficiency N – ↑ N – ↑ ↑ ↓ N

Factor VII deficiency ↑ N N N N

Factor VIII, IX, or XI deficiency

N ↑ N N N

Factor II, V, X deficiency ↑ ↑ N N N

Factor deficiencies not associated with bleeding (factor XII, high- molecular-weight kininogen or prekallikrein deficiency)

N ↑ N N N

Acquired hemophilia and congenital hemophilia with inhibitors

N ↑* N N N

Lupus anticoagulant N – ↑ N – ↑† N – ↑ N N

Heparin therapy or sample contamination

N – ↑ ↑ ↑↑ N N

Liver disease N – ↑ N – ↑ N – ↑ ↓ – N – ↑ ↓ – N

Vitamin K deficiency ↑ N – ↑ N N N

Fibrinolytic therapy ↑ ↑ ↑ ↓ N

Consumptive coagulopathy

N – ↑ ↑ ↑ ↓ ↓

Dilutional coagulopathy N – ↑ N – ↑ N – ↑ ↓ – N ↓

von Willebrand disease N N – ↑ N N N ↓ in type 2B and platelet type

Thrombocytopenia N N N N ↓

Platelet function disorders

N N N N ↓ – N

↑, elevated; ↓, reduced; APTT, activated partial thromboplastin time; N, normal; PT, prothrombin time. *An APTT of a 1:1 immediate mix of patient plasma containing a specific factor inhibitor and normal plasma can be N to ↑ depending on the features of their inhibitor. If a specific factor inhibitor is suspected, factor assays and tests for specific factor inhibitors should be performed. †APTT reagents have different sensitivities to lupus anticoagulants. A lupus anticoagulant usually prolongs the APTT with a 1:1 mix of patient and normal plasma.

To assess for VWD, a VWF antigen, VWF ristocetin cofactor activity, or newer VWF activity assays, and a factor VIII level should be ordered. The VWF level can be mildly low in blood group O individuals.

Platelet disorders are typically evaluated by specialized tests of platelet aggregation and secretion assays, which may require referral to a bleeding disorder specialist.

Additional tests can be helpful to evaluate if there is a history of acquired bleeding, which could reflect liver or renal disease or an endocrine disorder such as hypothyroidism or Cushing syndrome. As fibrinolytic defects are uncommon, testing is rarely done except by specialists.

PRACTICE POINT

In general, the patient’s symptoms, not the laboratory values, should be treated. Local factors can be significant contributors to bleeding and should be considered in the plans for investigation and treatment, even in patients with documented coagulopathies. Always consider risks and benefits (including those of treating or not treating) when deciding on appropriate therapies as the risks of certain therapies include increased prothrombotic risks. Patients with congenital bleeding disorders are best managed in a multidisciplinary care setting to plan treatment and prevention of acute bleeding episodes and to deal with complications (eg, hemophilic arthropathy). Information on the patient’s bleeding problem and the treatment plans must be communicated to both the patient and their health care providers.

HOW SHOULD THIS PATIENT WITH A BLEEDING DISORDER BE TREATED?

The management of each patient with a bleeding disorder depends on the cause and severity of their bleeding disorder.

GENERAL CONSIDERATIONS

The patient’s symptoms, not the laboratory values, should be treated. In general, treatment should be considered when the patient is bleeding or when the risk of bleeding is high (eg, if the patient is undergoing an invasive procedure). Local factors can be significant contributors to bleeding and should be considered in the plans for investigation and treatment, even in patients with documented coagulopathies.

It is necessary to consider risks and benefits (including those of treating or not treating) when deciding on appropriate therapies, as the risks of certain therapies include increased prothrombotic risks. Other risks of hemostatic therapies (for treatment or propylaxis) include risks for viral transmission (ie, with blood products; recombinant products are generally preferred over blood-derived products to minimize these risks), and hyponatremia (with desmopressin acetate, if fluid restriction is not imposed for 12 hours post-therapy). In addition, treatment plans need to consider whether standard treatments (eg, use of intramuscular injections, postoperative anticoagulants, anti- inflammatory drugs that inhibit platelet function) should be modified because of the patient’s bleeding problems. Information on the patient’s bleeding problem and the treatment plans must be communicated to both the patient and his health care providers. Patients with congenital bleeding disorders must be “taught” that prophylactic treatment is required prior to invasive procedures. Patients with congenital bleeding disorders are best managed in a multidisciplinary care setting to plan treatment and prevention of acute bleeding episodes and to deal with complications (eg, hemophilic arthropathy).

OTHER ISSUES TO CONSIDER FOR TREATMENT OF CONGENITAL BLEEDING DISORDERS

Treatments for factor deficiencies

Individuals with moderate-to-severe clinically significant factor deficiencies often require factor concentrates (recombinant products generally preferred over plasma-derived products), although some conditions and circumstances (eg, mild hemophilia due to factor VIII deficiency with mild bleeding) may be managed with desmopressin. Fibrinolytic inhibitor drugs (aminocaproic acid and tranexamic acid) are often used as an adjunctive therapy for some procedures, such as dental and oral-nasal surgeries. Fibrinolytic inhibitor drugs are the treatment of choice for fibrinolytic disorders.

von Willebrand disease

The treatment of VWD depends on the type and severity of the disease. With mild VWD, which is more common, treatment with desmopressin acetate may be sufficient for many situations. In general, the treatment goal is to raise the levels of VWF (by giving the medication desmopressin acetate or VWF concentrates) to normal.

Platelet function disorders

Most platelet function disorders are mild bleeding disorders that respond to treatment with desmopressin acetate, which enhances platelet procoagulant activity in addition to increasing plasma VWF levels. Other options for therapy include fibrinolytic inhibitors (eg, for menorrhagia, oral-nasal surgery, or dental extractions), platelet transfusions (reserved for rare, severe disorders, such as Glanzmann thrombasthenia and Bernard Soulier syndrome and also given when bleeding is serious and not adequately controlled by desmopressin), and sometimes activated factor VII concentrate (generally reserved for situations where there is a wish to avoid platelet transfusions and other drug therapies, such as desmopressin, are not adequate).

GENERAL MANAGEMENT OF COMMON ACQUIRED BLEEDING DISORDERS

Liver disease

The coagulopathy related to liver disease is multifactorial, as the liver is the major source of all hemostatic proteins in plasma except for VWF and tissue plasminogen activator. Individuals with liver disease often have deficiencies of multiple coagulation factors, and in mild liver disease, there can be low levels of factors VII and, at times, factors XI and XII. Fibrinogen deficiency is typically only seen with severe liver disease. In fact, fibrinogen levels are often elevated in mild liver disease. Sometimes patients with liver disease have additional hemostatic defects such as vitamin K deficiency, thrombocytopenia, dysfibrinogenemia, platelet function abnormalities, and disseminated intravascular coagulation (DIC). If an individual with coagulopathy from liver disease requires treatment (ie, for active bleeding or, in some instances, before a procedure associated with a significantly increased risk of bleeding), one or more of the following treatment options should be considered: vitamin K replacement (if deficient), plasma infusion (typically requires four or more units to have measurable effects), fibrinogen replacement (with cryoprecipitate or fibrinogen concentrate), and/or platelet transfusion. The role of prothrombin complex concentrates in patients with liver disease is uncertain.

Anticoagulant medications

Treatment of serious bleeding due to anticoagulants may require reversal of the anticoagulant. Patients on an oral vitamin K antagonist, who require reversal to treat bleeding, should receive vitamin K, and when more rapid reversal is required (eg, to treat life-threatening gastrointestinal bleeding), prothrombin complex concentrate (if available) or plasma infusion should be considered. Protamine sulfate can be considered when there is a need to rapidly reverse unfractionated heparin or low-molecular-weight heparin because of bleeding. However, this treatment reverses only about 60% of the antifactor Xa activity of low-molecular-weight heparin. Unfortunately, agents are not currently available to rapidly reverse some of the newer, novel anticoagulants that are direct inhibitors of thrombin or factor Xa. However, specific antidotes for direct thrombin inhibitors and factor Xa inhibitors have been developed and are undergoing clinical testing. It is unclear whether bleeding from these newer agents is improved by treatment with desmopressin acetate, fibrinolytic inhibitor drugs, or other treatments, such as prothrombin complex concentrates and factor VIIa.

Vitamin K deficiency

Acquired bleeding due to vitamin K deficiency results from decreased gamma- carboxylation of the vitamin K-dependent factors II, VII, IX, and X and can be treated by administration of vitamin K.

CONCLUSION

Abnormal bleeding in an important health care problem that should be suspected when bleeding occurs spontaneously is more severe than expected or occurs on repeated occasions.

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