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Tintinallirsquos Emergency Medicine A Comprehensive Study Guide 8e

Chapter 233 Chapter 233 Acquired Bleeding DisordersAcquired Bleeding Disorders Robert W Shaer Sally A Santen

INTRODUCTIONINTRODUCTION

Normal regulation of bleeding is a complex process involving platelets and the coagulation system (seechapter 232 Tests of Hemostasis) Platelet defects typically manifest with petechiae and mucosal bleedingwhereas coagulation defects usually present as spontaneous or excessive hemorrhage Management ofsignificant acquired bleeding disorders should be discussed with a hematologist because there are oensubtleties in diagnosis and treatment

ACQUIRED PLATELET DEFECTSACQUIRED PLATELET DEFECTS

Circulating platelets provide the initial defense against bleeding Acquired platelet disorders may bequantitative (decreased number of circulating platelets) or qualitative (poorly functioning platelets) Bothsignificant thrombocytopenia and qualitative platelet dysfunction are commonly manifested by the presenceof nonpalpable petechiae oen most pronounced in the lower extremities and in areas where blood flow isrestricted Other typical findings may include purpura mucosal bleeding (gingival epistaxis) menorrhagiahemoptysis hematuria and hematochezia whereas deep tissue bleeding and hemarthrosis are lesscommon

Securing circulatory stability is the primary treatment priority in the bleeding patient Once this is done thehistory physical examination and directed laboratory testing are used to define the clinical syndromeRecent illness symptoms and medications are potentially relevant in the patient who appears to have aplatelet disorder Physical examination should assess for additional bleeding sites and the type of bleedingAssess for lymphadenopathy splenomegaly pallor or jaundice that suggests diagnoses such as leukemialymphoma systemic lupus erythematosus infectious mononucleosis or hemolytic anemia

THROMBOCYTOPENIATHROMBOCYTOPENIA

Quantitative defects that result in thrombocytopenia are caused by decreased production increased

destruction splenic sequestration platelet loss or a combination (Table 233-1Table 233-1)1 The etiologies ofthrombocytopenia are diverse and the pathologic mechanism is not always initially clear Viral infectionsmay impair thrombopoiesis due to direct infection of the megakaryocyte toxic eects of viral proteins orcytokines hemophagocytosis or production of antibodies that bind to platelets and enhance immuneLoading [Contrib]a11yaccessibility-menujs

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Abbreviation HIV = human immunodeficiency virus

destruction2 A drug history is important because many medications have been implicated in causing

thrombocytopenia or impairing platelet function (Table 233-2Table 233-2)34

TABLE 233-1

Pathophysiology of Acquired ThrombocytopeniaPathophysiology of Acquired Thrombocytopenia

MechanismMechanism Associated Clinical ConditionsAssociated Clinical Conditions

Decreased platelet production Marrow infiltration (tumor or infection)

Viral infections (rubella HIV hepatitis C others)

Drugs (Table 233-2)

Radiation

Vitamin B12 andor folate deficiency

Increased platelet destruction Immune thrombocytopenia

Thrombotic thrombocytopenic purpura

Hemolytic-uremic syndrome

Disseminated intravascular coagulation

Viral infections (HIV mumps varicella Epstein-Barr virus)

Drugs (Table 233-2)

Platelet loss Excessive hemorrhage

Hemodialysis extracorporeal circulation

Splenic sequestration Sickle cell disease cirrhosis

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Note 4+ to 1+ indicates relative incidence from more frequent to less frequent based on case reports

TABLE 233-2

Drugs That Produce Thrombocytopenia or Impair Platelet FunctionDrugs That Produce Thrombocytopenia or Impair Platelet Function

Produce ThrombocytopeniaProduce Thrombocytopenia Impair FunctionImpair Function

Heparin 4+ Aspirin

Gold salts 4+ Nonsteroidal anti-inflammatory drugs

Sulfa-containing antibiotics 4+ Glycoprotein IIbndashIIIa agents ticlopidine and clopidogrel

Quinine and quinidine 4+

Ethanol (chronic use) 4+ Penicillins and cephalosporins

Aspirin 3+ Calcium channel blockers

Indomethacin 3+ β-Adrenergic blockers propranolol

Rifampin 2+ Nitroglycerin

Abciximab and eptifibatide 2+ Antihistamines

Thiazides and furosemide 2+ Phenothiazines

Acyclovir 2+ Cyclic antidepressants

Procainamide 2+

Digoxin 2+

Cimetidine and ranitidine 2+

Phenytoin and valproate 1+

Penicillinscephalosporins 1+

A CBC will establish the presence and degree of thrombocytopenia and determine whether otherhematologic cell lines are aected A peripheral smear should be examined to assess platelet morphologyLoading [Contrib]a11yaccessibility-menujs

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Note 4+ to 1+ indicates relative incidence from more frequent to less frequent based on case reports

TABLE 233-2

Drugs That Produce Thrombocytopenia or Impair Platelet FunctionDrugs That Produce Thrombocytopenia or Impair Platelet Function

Produce ThrombocytopeniaProduce Thrombocytopenia Impair FunctionImpair Function

Heparin 4+ Aspirin

Gold salts 4+ Nonsteroidal anti-inflammatory drugs

Sulfa-containing antibiotics 4+ Glycoprotein IIbndashIIIa agents ticlopidine and clopidogrel

Quinine and quinidine 4+

Ethanol (chronic use) 4+ Penicillins and cephalosporins

Aspirin 3+ Calcium channel blockers

Indomethacin 3+ β-Adrenergic blockers propranolol

Rifampin 2+ Nitroglycerin

Abciximab and eptifibatide 2+ Antihistamines

Thiazides and furosemide 2+ Phenothiazines

Acyclovir 2+ Cyclic antidepressants

Procainamide 2+

Digoxin 2+

Cimetidine and ranitidine 2+

Phenytoin and valproate 1+

Penicillinscephalosporins 1+

A CBC will establish the presence and degree of thrombocytopenia and determine whether otherhematologic cell lines are aected A peripheral smear should be examined to assess platelet morphologyLoading [Contrib]a11yaccessibility-menujs

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and evaluate other cell lines Rarely in vitro platelet agglutination occurs which leads to spuriously lowplatelet counts reported by automated cell counters (pseudothrombocytopenia) when collected inethylenediaminetetraacetic acidndashcoated blood tubes this can be detected by the presence of plateletclumping on a peripheral smear In this case a correct platelet count may be obtained by using citrated orheparin-anticoagulated blood tubes

Testing for human immunodeficiency virus and hepatitis C virus is recommended in cases of isolated

thrombocytopenia as low platelets may be the only readily apparent manifestation in early infections5 If theetiology of low platelets remains unclear further laboratory testing to evaluate for disorders such ashemolysis and disseminated intravascular coagulation (DIC) may be needed Although usually not necessaryin instances of isolated thrombocytopenia bone marrow biopsy may be obtained when malignancy or otherbone marrow pathologies are of concern

When circulating platelet levels decrease to below 10000 to 20000mm3 (10 to 20 times 109L) the risk ofspontaneous bleeding becomes concerning particularly for intracranial hemorrhage Additional risk factorsfor bleeding include age comorbid illness (ie renal disease liver disease connective tissue disease pepticulcer disease hypertension) fall risk and lifestyle activity With the exception of a few specific diseaseprocesses platelet transfusion in the nonbleeding patient should be considered when counts fall below

10000mm3 (10 times109L) or higher if other comorbid illnesses are present6 The cause of the plateletdeficiency may also influence the risk of bleeding At a given platelet level patients with immunethrombocytopenia (ITP) typically bleed less than patients with aplastic anemia as the younger platelets

present in ITP are more eective in hemostasis7

Immune Causes of ThrombocytopeniaImmune Causes of Thrombocytopenia

ITP is an acquired immune-mediated disorder in which circulating platelets typically fall to very low levels38

ITP results from antiplatelet antibodies that attack platelet surface glycoproteins such as glycoproteinIIbIIIa leading to peripheral platelet destruction There is evidence that the same antibodies lead to

impaired platelet production by megakaryocytes9 Despite very low platelet counts the circulating plateletsare not functionally impaired

Immune thrombocytopenia may be classified as primary (formerly known as idiopathic thrombocytopenicpurpura) or secondary when associated with other medical conditions (autoimmune disorders infections) or

drug exposures8 This distinction is of clinical importance as management of the underlying disorder ordiscontinuation of the drug in cases of secondary ITP may lead to normalization of the platelet count

Primary ITP may occur at any age with equal prevalence between genders with the exception of those age30 to 60 years in which women predominate Primary ITP is classified by duration of illness newly diagnosed

(diagnosis to 3 months) persistent (3 months to 12 months) and chronic (gt12 months)8 The majority ofadults with primary ITP progress to chronic illness

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The most common presenting sign of ITP is a petechial rash (Figure 233-1AFigure 233-1A) Mild epistaxis gingival bleeding(Figure 233-1BFigure 233-1B) and menorrhagia in women of childbearing age may also be seen Except for petechiae andbruising the patient should have a normal physical examination

FIGURE 233-1FIGURE 233-1

Two patients with idiopathic thrombocytopenic purpura AA Petechiae with platelet count of 3000mm3 (3 times

109L) BB Gingival bleeding with platelet count of 5000mm3 (5 times 109L) [Image used with permission of JStephan Stapczynski MD]

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The CBC should demonstrate normal cell lines except for the platelets A mild anemia may be seen if bleedingis present The peripheral smear should show large well-granulated platelets although they will be few innumber Bone marrow biopsy is not indicated unless clinical features are atypical If the evaluation supportsthe diagnosis of primary ITP then additional testing in the ED is not required

Treatment for ITP is initiated based on the risk of bleeding (Table 233-3Table 233-3) Major bleeding complications in

patients with platelets gt50000 mm3 (gt50 times 109L) are uncommon As most fatal bleeding complications

occur when platelet counts fall below 30000mm3 (30 times 109L) experts and guidelines recommend this level

as the threshold for initiating treatment of ITP in adults5691011 Bleeding risk correlates with lower plateletcounts and patient age greater than 60 a prior history of bleeding certain chronic illnesses and use ofmedications that alter hemostasis all heighten this risk Therefore certain patients may benefit from medical

treatment despite a platelet count exceeding 30000mm3 (30 times 109L) For all patients with primary ITPbleeding risk should be minimized including avoiding use of antiplatelet medications when possiblemaintenance of good blood pressure control optimized treatment of exacerbating comorbid conditions (ieliver disease renal disease) and addressing fall risks

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TABLE 233-3

Treatment of Immune ThrombocytopeniaTreatment of Immune Thrombocytopenia

Platelet

transfusionlt10000ndash20000mm3 (lt10ndash20 times 109L) prophylactically to prevent bleeding

lt50000mm3 (lt50 times 109L) if actively bleeding

lt20000ndash50000mm3 (lt20ndash50 times 109L) if patient requires diagnostic puncture

lt50000ndash100000mm3 (lt50ndash100 times 109L) if patient requires invasive procedure

Corticosteroids Prednisone 1 milligramkg PO per day for 21 days then tapered or dexamethasone 20

milligramsm2 IV per day for 4 d

IV

immunoglobulin

1 gramkg IV per day for 3 d

Splenectomy Considered for refractory cases

About two thirds of children with primary ITP will have spontaneous resolution within 6 months of

diagnosis11 An antecedent viral infection is commonly reported Additionally the measles-mumps-rubellavaccination has been associated with the development of acute ITP although this is rare and occurs in less

than 1 per 25000 doses given12 The risk of severe bleeding complications appears to be rare in children

regardless of their absolute platelet count5813 Children without signs of active bleeding and goodpsychosocial support typically do not require hospitalization or medical treatment Good anticipatoryguidance should be provided to the family and the child should abstain from contact sports or activities thatmight place them at risk for head injury

First-line treatment for primary ITP generally includes corticosteroids typically prednisone 1 milligramkg

per day for 4 weeks (shorter courses may be considered for children)59101113 Initial response may not beseen for 4 to 14 days and peak eect can be expected between 7 and 28 days IV immunoglobulin may alsobe considered either alone or in combination with corticosteroids at a dose 1 gkgper day for 3 days Initialresponse to IV immunoglobulin is more rapid than corticosteroids occurring between 1 and 3 days withpeak eect seen between 2 and 7 days Side eects of IV immunoglobulin may include aseptic meningitistransient neutropenia acute kidney injury and transfusion reactionshypotension

Anti-Rho(D) immunoglobulin at 50 to 75 microgramskg for a single dose may also be considered as a first-

line treatment strategy in patients who are Rh(D) positive and have not undergone splenectomy14 Initialresponse rate and peak eect are similar to that seen with IV immunoglobulin Mild hemolysis can beexpected and rare serious or even fatal cases of intravascular hemolysis DIC and renal failure have beenreported with anti-Rho(D) use prompting the US Food and Drug Administration to administer a warningLoading [Contrib]a11yaccessibility-menujs

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The most common presenting sign of ITP is a petechial rash (Figure 233-1AFigure 233-1A) Mild epistaxis gingival bleeding(Figure 233-1BFigure 233-1B) and menorrhagia in women of childbearing age may also be seen Except for petechiae andbruising the patient should have a normal physical examination

FIGURE 233-1FIGURE 233-1

Two patients with idiopathic thrombocytopenic purpura AA Petechiae with platelet count of 3000mm3 (3 times

109L) BB Gingival bleeding with platelet count of 5000mm3 (5 times 109L) [Image used with permission of JStephan Stapczynski MD]

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The CBC should demonstrate normal cell lines except for the platelets A mild anemia may be seen if bleedingis present The peripheral smear should show large well-granulated platelets although they will be few innumber Bone marrow biopsy is not indicated unless clinical features are atypical If the evaluation supportsthe diagnosis of primary ITP then additional testing in the ED is not required

Treatment for ITP is initiated based on the risk of bleeding (Table 233-3Table 233-3) Major bleeding complications in

patients with platelets gt50000 mm3 (gt50 times 109L) are uncommon As most fatal bleeding complications

occur when platelet counts fall below 30000mm3 (30 times 109L) experts and guidelines recommend this level

as the threshold for initiating treatment of ITP in adults5691011 Bleeding risk correlates with lower plateletcounts and patient age greater than 60 a prior history of bleeding certain chronic illnesses and use ofmedications that alter hemostasis all heighten this risk Therefore certain patients may benefit from medical

treatment despite a platelet count exceeding 30000mm3 (30 times 109L) For all patients with primary ITPbleeding risk should be minimized including avoiding use of antiplatelet medications when possiblemaintenance of good blood pressure control optimized treatment of exacerbating comorbid conditions (ieliver disease renal disease) and addressing fall risks

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TABLE 233-3

Treatment of Immune ThrombocytopeniaTreatment of Immune Thrombocytopenia

Platelet

transfusionlt10000ndash20000mm3 (lt10ndash20 times 109L) prophylactically to prevent bleeding

lt50000mm3 (lt50 times 109L) if actively bleeding

lt20000ndash50000mm3 (lt20ndash50 times 109L) if patient requires diagnostic puncture

lt50000ndash100000mm3 (lt50ndash100 times 109L) if patient requires invasive procedure

Corticosteroids Prednisone 1 milligramkg PO per day for 21 days then tapered or dexamethasone 20

milligramsm2 IV per day for 4 d

IV

immunoglobulin

1 gramkg IV per day for 3 d

Splenectomy Considered for refractory cases

About two thirds of children with primary ITP will have spontaneous resolution within 6 months of

diagnosis11 An antecedent viral infection is commonly reported Additionally the measles-mumps-rubellavaccination has been associated with the development of acute ITP although this is rare and occurs in less

than 1 per 25000 doses given12 The risk of severe bleeding complications appears to be rare in children

regardless of their absolute platelet count5813 Children without signs of active bleeding and goodpsychosocial support typically do not require hospitalization or medical treatment Good anticipatoryguidance should be provided to the family and the child should abstain from contact sports or activities thatmight place them at risk for head injury

First-line treatment for primary ITP generally includes corticosteroids typically prednisone 1 milligramkg

per day for 4 weeks (shorter courses may be considered for children)59101113 Initial response may not beseen for 4 to 14 days and peak eect can be expected between 7 and 28 days IV immunoglobulin may alsobe considered either alone or in combination with corticosteroids at a dose 1 gkgper day for 3 days Initialresponse to IV immunoglobulin is more rapid than corticosteroids occurring between 1 and 3 days withpeak eect seen between 2 and 7 days Side eects of IV immunoglobulin may include aseptic meningitistransient neutropenia acute kidney injury and transfusion reactionshypotension

Anti-Rho(D) immunoglobulin at 50 to 75 microgramskg for a single dose may also be considered as a first-

line treatment strategy in patients who are Rh(D) positive and have not undergone splenectomy14 Initialresponse rate and peak eect are similar to that seen with IV immunoglobulin Mild hemolysis can beexpected and rare serious or even fatal cases of intravascular hemolysis DIC and renal failure have beenreported with anti-Rho(D) use prompting the US Food and Drug Administration to administer a warningLoading [Contrib]a11yaccessibility-menujs

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The CBC should demonstrate normal cell lines except for the platelets A mild anemia may be seen if bleedingis present The peripheral smear should show large well-granulated platelets although they will be few innumber Bone marrow biopsy is not indicated unless clinical features are atypical If the evaluation supportsthe diagnosis of primary ITP then additional testing in the ED is not required

Treatment for ITP is initiated based on the risk of bleeding (Table 233-3Table 233-3) Major bleeding complications in

patients with platelets gt50000 mm3 (gt50 times 109L) are uncommon As most fatal bleeding complications

occur when platelet counts fall below 30000mm3 (30 times 109L) experts and guidelines recommend this level

as the threshold for initiating treatment of ITP in adults5691011 Bleeding risk correlates with lower plateletcounts and patient age greater than 60 a prior history of bleeding certain chronic illnesses and use ofmedications that alter hemostasis all heighten this risk Therefore certain patients may benefit from medical

treatment despite a platelet count exceeding 30000mm3 (30 times 109L) For all patients with primary ITPbleeding risk should be minimized including avoiding use of antiplatelet medications when possiblemaintenance of good blood pressure control optimized treatment of exacerbating comorbid conditions (ieliver disease renal disease) and addressing fall risks

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TABLE 233-3

Treatment of Immune ThrombocytopeniaTreatment of Immune Thrombocytopenia

Platelet

transfusionlt10000ndash20000mm3 (lt10ndash20 times 109L) prophylactically to prevent bleeding

lt50000mm3 (lt50 times 109L) if actively bleeding

lt20000ndash50000mm3 (lt20ndash50 times 109L) if patient requires diagnostic puncture

lt50000ndash100000mm3 (lt50ndash100 times 109L) if patient requires invasive procedure

Corticosteroids Prednisone 1 milligramkg PO per day for 21 days then tapered or dexamethasone 20

milligramsm2 IV per day for 4 d

IV

immunoglobulin

1 gramkg IV per day for 3 d

Splenectomy Considered for refractory cases

About two thirds of children with primary ITP will have spontaneous resolution within 6 months of

diagnosis11 An antecedent viral infection is commonly reported Additionally the measles-mumps-rubellavaccination has been associated with the development of acute ITP although this is rare and occurs in less

than 1 per 25000 doses given12 The risk of severe bleeding complications appears to be rare in children

regardless of their absolute platelet count5813 Children without signs of active bleeding and goodpsychosocial support typically do not require hospitalization or medical treatment Good anticipatoryguidance should be provided to the family and the child should abstain from contact sports or activities thatmight place them at risk for head injury

First-line treatment for primary ITP generally includes corticosteroids typically prednisone 1 milligramkg

per day for 4 weeks (shorter courses may be considered for children)59101113 Initial response may not beseen for 4 to 14 days and peak eect can be expected between 7 and 28 days IV immunoglobulin may alsobe considered either alone or in combination with corticosteroids at a dose 1 gkgper day for 3 days Initialresponse to IV immunoglobulin is more rapid than corticosteroids occurring between 1 and 3 days withpeak eect seen between 2 and 7 days Side eects of IV immunoglobulin may include aseptic meningitistransient neutropenia acute kidney injury and transfusion reactionshypotension

Anti-Rho(D) immunoglobulin at 50 to 75 microgramskg for a single dose may also be considered as a first-

line treatment strategy in patients who are Rh(D) positive and have not undergone splenectomy14 Initialresponse rate and peak eect are similar to that seen with IV immunoglobulin Mild hemolysis can beexpected and rare serious or even fatal cases of intravascular hemolysis DIC and renal failure have beenreported with anti-Rho(D) use prompting the US Food and Drug Administration to administer a warningLoading [Contrib]a11yaccessibility-menujs

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TABLE 233-3

Treatment of Immune ThrombocytopeniaTreatment of Immune Thrombocytopenia

Platelet

transfusionlt10000ndash20000mm3 (lt10ndash20 times 109L) prophylactically to prevent bleeding

lt50000mm3 (lt50 times 109L) if actively bleeding

lt20000ndash50000mm3 (lt20ndash50 times 109L) if patient requires diagnostic puncture

lt50000ndash100000mm3 (lt50ndash100 times 109L) if patient requires invasive procedure

Corticosteroids Prednisone 1 milligramkg PO per day for 21 days then tapered or dexamethasone 20

milligramsm2 IV per day for 4 d

IV

immunoglobulin

1 gramkg IV per day for 3 d

Splenectomy Considered for refractory cases

About two thirds of children with primary ITP will have spontaneous resolution within 6 months of

diagnosis11 An antecedent viral infection is commonly reported Additionally the measles-mumps-rubellavaccination has been associated with the development of acute ITP although this is rare and occurs in less

than 1 per 25000 doses given12 The risk of severe bleeding complications appears to be rare in children

regardless of their absolute platelet count5813 Children without signs of active bleeding and goodpsychosocial support typically do not require hospitalization or medical treatment Good anticipatoryguidance should be provided to the family and the child should abstain from contact sports or activities thatmight place them at risk for head injury

First-line treatment for primary ITP generally includes corticosteroids typically prednisone 1 milligramkg

per day for 4 weeks (shorter courses may be considered for children)59101113 Initial response may not beseen for 4 to 14 days and peak eect can be expected between 7 and 28 days IV immunoglobulin may alsobe considered either alone or in combination with corticosteroids at a dose 1 gkgper day for 3 days Initialresponse to IV immunoglobulin is more rapid than corticosteroids occurring between 1 and 3 days withpeak eect seen between 2 and 7 days Side eects of IV immunoglobulin may include aseptic meningitistransient neutropenia acute kidney injury and transfusion reactionshypotension

Anti-Rho(D) immunoglobulin at 50 to 75 microgramskg for a single dose may also be considered as a first-

line treatment strategy in patients who are Rh(D) positive and have not undergone splenectomy14 Initialresponse rate and peak eect are similar to that seen with IV immunoglobulin Mild hemolysis can beexpected and rare serious or even fatal cases of intravascular hemolysis DIC and renal failure have beenreported with anti-Rho(D) use prompting the US Food and Drug Administration to administer a warningLoading [Contrib]a11yaccessibility-menujs

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pertaining to its use in 2010 Second-line treatment modalities include splenectomy and use of neweragents such as the monoclonal antibody rituximab which blunts the autoimmune destruction of plateletsand thrombopoietin receptor agonists which stimulate platelet production (ie romiplostin eltrombopag)

In the event of life-threatening hemorrhage where hemostasis must be achieved rapidly IV corticosteroids

(such as dexamethasone) and IV immunoglobulin should be administered concomitantly13 Platelettransfusions should be initiated and doses two to three times the typical dose might be required due to

persistent autoimmune destruction6 Platelet transfusions may need to be repeated frequently until bleedingsubsides or targeted treatment modalities take eect Emergent splenectomy may be considered if all othertreatment options are exhausted

Drug-Induced Immune ThrombocytopeniaDrug-Induced Immune Thrombocytopenia

Over 200 drugs have been implicated in causing immune-mediated suppression of platelet production or

increased platelet destruction (Table 233-2)34 The clinical presentation is similar to ITP and thethrombocytopenia may severe Drug-induced thrombocytopenia typically occurs 5 to 14 days followinginitiation of a drug but may occur sooner if there has been recent prior exposure A careful history should notonly include prescribed medications but also herbal remedies and food and beverage use (ie quinine intonic water alcohol use tahini) Chronic alcohol use is a common cause of thrombocytopenia Plateletcounts typically normalize with cessation of the causative agent Heparin-induced thrombocytopenia causesa significant drop in platelets but patients are paradoxically hypercoagulable due to platelet activation (seechapter 239 Thrombotics and Antithrombotics)

Nonimmune Causes of ThrombocytopeniaNonimmune Causes of Thrombocytopenia

Thrombocytopenia may occur from various nonndashimmune-mediated causes (Table 233-1) In thromboticthrombocytopenic purpura and hemolytic-uremic syndrome thrombotic microangiopathy occurs whenvessel injury results in deposition of platelet-fibrin thrombi (see chapters 143 Oncologic and HematologicEmergencies in Children and 237 Acquired Hemolytic Anemia) DIC is also a well-described cause ofplatelet destruction In patients with marked hemorrhage large-volume fluid resuscitation may lead to adilutional thrombocytopenia Additionally certain bacterial rickettsial and viral infections can cause directtoxic destruction of platelets Thrombocytopenia specific to pregnancy may be a result of the hemolysisndashelevated liver enzymesndashlow platelets (HELLP) syndrome pre-eclampsia or gestational thrombocytopenia(see chapter 100 Maternal Emergencies aer 20 Weeks of Pregnancy and in the Postpartum Period)Finally an enlarged spleen can sequester a significant portion of the platelet pool

Thrombocytopenia is present in up to 70 of patients with chronic liver disease15 The etiology appearsmultifactorial Patients oen have underlying medical conditions related to their liver disease such as alcoholuse viral hepatitis or nutritional deficiencies that impair platelet production Thrombopoietin which isproduced by hepatocytes may be decreased Portal hypertension may lead to splenic sequestrationEndotoxemia from infection may promote platelet aggregation Some patients also demonstrate plateletLoading [Contrib]a11yaccessibility-menujs

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autoantibodies The degree of quantitative thrombocytopenia may be mitigated by an increased level ofcirculating von Willebrand factor that is typically seen which promotes platelet adhesion For this reasonroutine platelet transfusion is not recommended in the absence of clinically significant bleeding However a

platelet count of gt50000mm3 (gt50 times 109L) should be achieved prior to invasive procedures (ie lumbar

puncture surgery liver biopsy)16

FUNCTIONAL PLATELET DISORDERSFUNCTIONAL PLATELET DISORDERS

Several disease processes can cause acquired qualitative or functional abnormalities of platelets (Table 233-Table 233-

44)17 In the myeloproliferative diseases platelets are oen dysfunctional even if the platelet count is normalor elevated Patients can have prolonged bleeding times and clinically significant bleeding To control acute

bleeding transfusion should be considered to raise the level of normal platelets to 50000mm3 (50 times 109L)In macroglobulinemia and related disorders the elevated level of viscous proteins interferes with plateletfunction Patients with clinically significant bleeding may require plasmapheresis to reduce the protein leveland correct hemostatic function

TABLE 233-4

Clinical Conditions Associated with Qualitative Platelet AbnormalitiesClinical Conditions Associated with Qualitative Platelet Abnormalities

Uremia

Liver disease

Disseminated intravascular coagulation

Antiplatelet antibodies (immune thrombocytopenia systemic lupus erythematosus)

Cardiopulmonary bypass

Myeloproliferative disorders (thrombocytosis polycythemia vera chronic myeloid leukemia acute

lymphocytic or myelogenous leukemia)

Dysproteinemias (multiple myeloma Waldenstroumlms macroglobulinemia)

von Willebrands disease (congenital or acquired)

Many drugs can influence platelet function (Table 233-2 and Table 233-5Table 233-5) Of these the most commonly usedare aspirin which produces an irreversible impairment in platelet aggregation and the nonsteroidal anti-inflammatory drugs clopidogrel and ticlopidine which produce temporary impairment in platelet adhesionand aggregation (see chapter 239)

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TABLE 233-5

Duration of Antiplatelet ActivityDuration of Antiplatelet Activity

DrugDrug OnsetOnset Duration of EectDuration of Eect

Aspirin 1 h Up to 7 d

Most nonsteroidal anti-inflammatory drugs 1 h 1 d

Piroxicam 1 h 2 d

Ticlopidine or clopidogrel 1ndash2 d 4ndash7 d

Thrombocytosis a platelet count exceeding 500000mm3 (500 times 109L) can be seen in many disordersincluding inflammatory reactions malignancy polycythemia and postsplenectomy Platelet function can benormal or abnormal depending on the underlying condition Therefore thrombocytosis can be associatedwith bleeding (mucosal ecchymotic GI) or thromboembolic (deep venous thrombosis portal or mesentericthrombosis splenic vein thrombosis) manifestations However these events are unusual even with platelet

counts in excess of 1000000mm3 (1000 times 109L)

ACQUIRED COAGULATION DISORDERSACQUIRED COAGULATION DISORDERS

Acquired coagulation disorders can result from underlying medical disease and autoimmune factorinhibitors

LIVER DISEASELIVER DISEASE

Acute and chronic liver disease is commonly associated with laboratory tests of impaired coagulationHepatocytes synthesize all of the coagulation factors and related regulatory proteins with the exception offactor VIII and von Willebrand factor Diseases aecting the hepatic parenchyma may result in a decreasedsynthesis of these factors including the vitamin Kndashdependent carboxylation of factors II (prothrombin) VIIIX and X Because vitamin K is a fat-soluble vitamin malabsorption can occur with processes that interferewith the absorption of fat-soluble vitamins including impaired bile acid metabolism (ie primary biliarycirrhosis) intrahepatic or extrahepatic cholestasis and treatment with bile acid binders Thus prolongedprothrombin time is common in patients with decompensated hepatic function Despite markedprolongations of prothrombin time and activated partial thromboplastin time (PTT) seen in advanced liverdisease and cirrhosis these tests poorly predict onset and severity of bleeding including bleeding from

esophageal varices or invasive procedures or surgery16181920 Although there may be marked reduction inprocoagulant proteins in liver disease there is typically a parallel decrease in the endogenous anticoagulantLoading [Contrib]a11yaccessibility-menujs

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proteins such as protein C and antithrombin Therefore primary hemostasis may be relatively maintained Infact patients with liver disease may be susceptible to both increased bleeding and thrombosis Patients withliver disease and cirrhosis are twice as likely to develop unprovoked deep venous thrombosis and have a

relatively high incidence of portal venous thrombosis21

In the actively bleeding patient with liver disease attention to volume and circulatory status is paramountTransfusion of packed red blood cells should be used to maintain an adequate hemoglobin andhemodynamic stability Fresh frozen plasma transfusions or platelets should be transfused if significanthemorrhage (eg from esophageal varices) is associated with a coagulopathy or thrombocytopenia with a

platelet count below 60000mm3 (60 times 109L)16 Plasma transfusions should be used cautiously becausethey may incite thrombosis and expand intravascular volume exacerbating portal hypertension andincreasing the severity of variceal bleeding There is no evidence that recombinant activated factor VII or

four-factor prothrombin complex concentrate (Kcentrareg) provides benefit22 The benefit of vitamin K in these

patients has also been called into question and its routine use is not substantiated2223

Primary prevention of bleeding in patients with liver disease should focus on medical optimization of their

risk factors rather than treatment of abnormal tests of coagulation or thrombocytopenia1618 These includemanagement and prevention of portal hypertension treatment of esophageal varices management ofprimary causes for liver disease (ie alcohol use hepatitis C) optimization of renal function andmanagement and prevention of sepsisinfection

RENAL DISEASERENAL DISEASE

Patients with renal disease frequently manifest disorders of hemostasis Early renal impairment has beenassociated with a tendency for thrombosis relating to increased production of procoagulant factors as well as

decreased formation of tissue plasminogen activator24 In advanced renal disease bleeding complicationsare of particular concern due to qualitative platelet dysfunction from decreased ability to adhere to damagedendothelium and aggregate Patients with chronic kidney disease are at increased risk for minor bleeding(mucosal and cutaneous) and major bleeding (intracerebral and GI hemorrhage) Serum prothrombin timeactivated PTT and platelet counts are oen normal although bleeding time will usually be prolongedAbnormalities in platelet function can be due to direct eects of uremic toxins and impaired drugelimination Anemia itself has been associated with platelet dysfunction Thrombocytopenia can occur fromdialysis and the heparin used may also potentiate bleeding

Desmopressin is the most common agent used to correct bleeding in patients with uremic plateletdysfunction producing an increase in serum von Willebrand factor and enhancing the platelets ability to

aggregate25 The dose is 03 milligramkg SC or IV with a rapid onset and duration of action lasting at least 4hours Side eects are generally mild and include headache flushing minor hypotension tachycardianausea abdominal cramps and local site reaction Other strategies that improve platelet function includethe use of cryoprecipitate conjugated estrogens erythropoietin to improve anemia and hemodialysis to

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remove toxins24 Platelet transfusions alone are generally ineective because the infused platelets quicklyacquire the platelet defect Cryoprecipitate and platelet transfusions should be reserved for life-threateningbleeding and should be used in combination with packed red blood cells desmopressin and conjugatedestrogens

DISSEMINATED INTRAVASCULAR COAGULATIONDISSEMINATED INTRAVASCULAR COAGULATION

DIC is an acquired syndrome characterized by inappropriate and widespread activation of the coagulationsystem resulting in intravascular thrombin generation small vessel thrombosis and consumption of clotting

factors and platelets26 Concomitant activation of the fibrinolytic system also occurs resulting in thebreakdown of fibrin clots and subsequent bleeding DIC is associated with a wide variety of precipitatingdisorders (Table 233-6Table 233-6)

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TABLE 233-6

Common Conditions Associated with Disseminated Intravascular Coagulation (DIC)Common Conditions Associated with Disseminated Intravascular Coagulation (DIC)

Clinical SettingClinical Setting CommentsComments

Infection

Bacterial

Viral

Fungal

Probably the most common cause of DIC 10ndash20 of patients with gram-negative

sepsis have DIC endotoxins stimulate monocytes and endothelial cells to express tissue

factor Rocky Mountain spotted fever causes direct endothelial damage DIC more likely

to develop in asplenic patients or cirrhosis septic patients are more likely to have

thrombosis than bleeding

Carcinoma

Adenocarcinoma

Lymphoma

Malignant cells may cause endothelial damage and allow the expression of tissue factor

as well as other procoagulant materials most adenocarcinomas tend to have thrombosis

(Trousseaus syndrome) whereas prostate cancer tends to have more bleeding DIC is

oen chronic and compensated

Acute leukemia DIC most common with promyelocytic leukemia blast cells release procoagulant

enzymes there is excessive release at time of cell lysis (chemotherapy) more likely to

have bleeding than thrombosis

Trauma DIC especially with brain injury crush injury burns hypothermia hyperthermia

rhabdomyolysis fat embolism hypoxia Massive bleeding can occur

Organ injury

Liver disease

Pancreatitis

May have chronic compensated DIC acute DIC may occur in the setting of acute hepatic

failure tissue factor is released from the injured hepatocytes Pancreatitis can activate

the coagulation cascade

Pregnancy Placental abruption amniotic fluid embolus septic abortion intrauterine fetal death

(can be chronic DIC) can have DIC in hemolysisndashelevated liver enzymesndashlow platelets

(HELLP) syndrome

Vascular disease Large aortic aneurysms (chronic DIC can become acute at time of surgery) giant

hemangiomas vasculitis multiple telangiectasias

Envenomation DIC can develop with bites of rattlesnakes and other vipers the venom damages the

endothelial cells bleeding is not as serious as expected from laboratory values

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Clinical SettingClinical Setting CommentsComments

Acute lung injury

(ALI) or adult

respiratory

distress

syndrome

Microthrombi are deposited in the small pulmonary vessels the pulmonary capillary

endothelium is damaged 20 of patients with ALI develop DIC and 20 of patients with

DIC develop ALI

Transfusion

reactions such

as acute

hemolytic

reaction

DIC with severe bleeding shock and acute renal failure

PathogenesisPathogenesis

Although the diseases triggering DIC are diverse the common pathway of these illnesses is that they lead toan inappropriate loss of localization or compensated control in the intravascular activation of coagulation(Figure 233-2Figure 233-2) Immune inflammatory and coagulant pathways are involved Damaged endothelial cell wallstrigger activation of the intrinsic clotting cascade leading to thrombin generation and subsequentintravascular fibrin clot deposition Increased thrombin generation leads to consumption of anticoagulantregulatory proteins (ie protein C protein S and antithrombin) further potentiating thrombosis andischemic tissue damage Production of thrombin and fibrin indirectly activates tissue plasminogen activatorand the counterregulatory fibrinolytic system When hyperfibrinolysis occurs the hemostatic clots dissolveand bleeding ensues

FIGURE 233-2FIGURE 233-2

Pathophysiology of disseminated intravascular coagulation Refer to Pathogenesis section underDisseminated Intravascular Coagulation for details FDPs = fibrinfibrinogen degradation products

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Clinical SettingClinical Setting CommentsComments

Acute lung injury

(ALI) or adult

respiratory

distress

syndrome

Microthrombi are deposited in the small pulmonary vessels the pulmonary capillary

endothelium is damaged 20 of patients with ALI develop DIC and 20 of patients with

DIC develop ALI

Transfusion

reactions such

as acute

hemolytic

reaction

DIC with severe bleeding shock and acute renal failure

PathogenesisPathogenesis

Although the diseases triggering DIC are diverse the common pathway of these illnesses is that they lead toan inappropriate loss of localization or compensated control in the intravascular activation of coagulation(Figure 233-2Figure 233-2) Immune inflammatory and coagulant pathways are involved Damaged endothelial cell wallstrigger activation of the intrinsic clotting cascade leading to thrombin generation and subsequentintravascular fibrin clot deposition Increased thrombin generation leads to consumption of anticoagulantregulatory proteins (ie protein C protein S and antithrombin) further potentiating thrombosis andischemic tissue damage Production of thrombin and fibrin indirectly activates tissue plasminogen activatorand the counterregulatory fibrinolytic system When hyperfibrinolysis occurs the hemostatic clots dissolveand bleeding ensues

FIGURE 233-2FIGURE 233-2

Pathophysiology of disseminated intravascular coagulation Refer to Pathogenesis section underDisseminated Intravascular Coagulation for details FDPs = fibrinfibrinogen degradation products

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Clinical FeaturesClinical Features

Clinical features of DIC vary with the underlying precipitating illness27 Hypercoagulation may predominatein certain conditions such as sepsis where signs of ischemic end-organ failure are common and physicalfindings in these patients may include cutaneous gangrene or thrombotic purpura In other instances such asDIC associated with leukemia hyperfibrinolysis may predominate and clinical features may includepetechiae ecchymoses oozing from catheter or venipuncture sites or hematuria Certain DIC-relateddisorders such as trauma and obstetric complications tend to have both strong hypercoagulation andhyperfibrinolysis elements and lead to major bleeding complications (ie wounds intracranial GI) Yet otherconditions may be associated with mild and compensated DIC in which outward signs of thrombosis andbleeding are subclinical

Laboratory FindingsLaboratory Findings

The typical laboratory results in acute DIC (Table 233-7Table 233-7) include thrombocytopenia prolonged prothrombintime low fibrinogen level and elevation of fibrin-related markers (ie d-dimer fibrin degradation products

soluble fibrin) The most commonly observed abnormality is thrombocytopenia a progressive drop in theplatelet count is sensitive although not specific for DIC Depletion of coagulation factors is reflected by aprolonged prothrombin time Fibrinogen is an acute-phase reactant and may be normal or elevated in early

DIC Scoring systems have been developed and validated to aid in the diagnosis (Table 233-8Table 233-8)2829

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Levels may be chronically elevated in patients with liver or renal disease

TABLE 233-7

Laboratory Abnormalities Characteristic of Disseminated Intravascular Coagulation (DIC)Laboratory Abnormalities Characteristic of Disseminated Intravascular Coagulation (DIC)2828

StudiesStudies ResultResult

Most UsefulMost Useful

Platelet count Usually low or dropping

Prothrombin time Prolonged

Fibrinogen level Usually low (fibrinogen is an acute-phase reactant so may actually start out

elevated) fibrinogen level lt100 milligramsdL (lt1 gramL) correlates with severe DIC

Fibrin degradation

products and d-

dimer

Elevated

HelpfulHelpful

Activated partial

thromboplastin time

Usually prolonged

Thrombin clotting

time

Prolonged (not sensitive)

Fragmented red

blood cells

Should be present (not specific)

Specific factor

assays

Extrinsic pathway factors are most aected (VII X V and II)

Factor II V VIIdagger X Low

Factor VIII (acute-

phase reactant)

Low normal high

Factor IX Low (decreases later than other factors)

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Levels may be chronically elevated in patients with liver or renal disease

TABLE 233-7

Laboratory Abnormalities Characteristic of Disseminated Intravascular Coagulation (DIC)Laboratory Abnormalities Characteristic of Disseminated Intravascular Coagulation (DIC)2828

StudiesStudies ResultResult

Most UsefulMost Useful

Platelet count Usually low or dropping

Prothrombin time Prolonged

Fibrinogen level Usually low (fibrinogen is an acute-phase reactant so may actually start out

elevated) fibrinogen level lt100 milligramsdL (lt1 gramL) correlates with severe DIC

Fibrin degradation

products and d-

dimer

Elevated

HelpfulHelpful

Activated partial

thromboplastin time

Usually prolonged

Thrombin clotting

time

Prolonged (not sensitive)

Fragmented red

blood cells

Should be present (not specific)

Specific factor

assays

Extrinsic pathway factors are most aected (VII X V and II)

Factor II V VIIdagger X Low

Factor VIII (acute-

phase reactant)

Low normal high

Factor IX Low (decreases later than other factors)

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daggerFactor VII is usually low early because it has the shortest half-life

Note A score of ge5 is compatible with overt DIC A score lt5 is suggestive (not airmative) for nonovert DIC

TABLE 233-8

International Society on Thrombosis and Haemostasis Scoring System for DIC When Associated Condition Known toInternational Society on Thrombosis and Haemostasis Scoring System for DIC When Associated Condition Known toCause Disseminated Intravascular Coagulation (DIC) Is PresentCause Disseminated Intravascular Coagulation (DIC) Is Present2929

TestTest PointsPoints

Platelet count

gt100000mm3 (gt100 times 109L) 0

50000ndash100000mm3 (50ndash100 times 109L) 1

lt50000mm3 (lt50 times 109L) 2

Fibrin-related marker (d-dimer fibrin degradation products)

Normal 0

Mildly elevated 2

Markedly elevated 3

Prothrombin time prolongation

lt3 s 0

3ndash6 s 1

gt6 s 2

Fibrinogen level

gt100 milligramsdL (gt1 gramL) 0

lt100 milligramsdL (lt1 gramL) 1

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Abbreviations aPTT = activated partial thromboplastin time LMWH = low molecular weight heparin PT = prothrombin

time

Dierential DiagnosisDierential Diagnosis

Primary fibrinolysis is a rare syndrome whereby plasmin and fibrinolysis occur without the production ofthrombin Severe liver disease will also manifest with coagulation abnormalities and low platelets These twoentities can be dierentiated from DIC based on clinical history and laboratory tests The hematologicabnormalities in liver disease should be relatively stable in contrast to the worsening abnormalitiesassociated with acute DIC Additionally the d-dimer assay will usually be normal or minimally elevated in

both primary fibrinolysis and liver disease but is oen significantly elevated in DIC

TreatmentTreatment

Paramount to the management of DIC is the elimination of the underlying disorder whenever possibleTreatment strategies in DIC include blood product support and strategies to modulate thrombin formation

(Table 233-9Table 233-9)262729 Generally speaking blood products should only be administered when there is evidenceof bleeding

TABLE 233-9

Treatment of Disseminated Intravascular Coagulation (DIC)Treatment of Disseminated Intravascular Coagulation (DIC)

Treat underlying precipitating disorder volume resuscitation antibiotics external cooling

Platelet transfusions for thrombocytopenia lt50000mm3 (lt50 times 109L) and active bleeding

Fresh frozen plasma for prolonged PT or aPTT (gt15) or low fibrinogen (lt100 milligramsdL [1 gramL])

Fibrinogen concentrate for persistent low fibrinogen lt100 milligramsdL (lt1 gramL)

Vitamin K for prolonged PT

Consider LMWH when thrombotic events dominate clinical picture

Consider tranexamic acid for trauma-related DIC

Platelet transfusions are recommended in actively bleeding patients who have platelet counts below

50000mm3 (50 times 109L) and may be considered in those considered to be at high risk for bleeding (such as

DIC resulting from chemotherapy) when platelet counts fall below 10000 to 20000mm3 (10 to 20 times 109L)Plasma should be administered in bleeding patients when prothrombin timeactivated PTT exceeds 15 timesnormal or when fibrinogen levels fall below 150 milligramsdL (15 gramsL) The initial recommended doseis 15 mLkg although there is some evidence that 30 mLkg may be superior when volume overload is not ofconcern Fibrinogen concentrate should be considered when hypofibrinogenemia persists despite use ofplasma Patients with a prolonged prothrombin time should receive parenteral vitamin K

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Abbreviations aPTT = activated partial thromboplastin time LMWH = low molecular weight heparin PT = prothrombin

time

Dierential DiagnosisDierential Diagnosis

Primary fibrinolysis is a rare syndrome whereby plasmin and fibrinolysis occur without the production ofthrombin Severe liver disease will also manifest with coagulation abnormalities and low platelets These twoentities can be dierentiated from DIC based on clinical history and laboratory tests The hematologicabnormalities in liver disease should be relatively stable in contrast to the worsening abnormalitiesassociated with acute DIC Additionally the d-dimer assay will usually be normal or minimally elevated in

both primary fibrinolysis and liver disease but is oen significantly elevated in DIC

TreatmentTreatment

Paramount to the management of DIC is the elimination of the underlying disorder whenever possibleTreatment strategies in DIC include blood product support and strategies to modulate thrombin formation

(Table 233-9Table 233-9)262729 Generally speaking blood products should only be administered when there is evidenceof bleeding

TABLE 233-9

Treatment of Disseminated Intravascular Coagulation (DIC)Treatment of Disseminated Intravascular Coagulation (DIC)

Treat underlying precipitating disorder volume resuscitation antibiotics external cooling

Platelet transfusions for thrombocytopenia lt50000mm3 (lt50 times 109L) and active bleeding

Fresh frozen plasma for prolonged PT or aPTT (gt15) or low fibrinogen (lt100 milligramsdL [1 gramL])

Fibrinogen concentrate for persistent low fibrinogen lt100 milligramsdL (lt1 gramL)

Vitamin K for prolonged PT

Consider LMWH when thrombotic events dominate clinical picture

Consider tranexamic acid for trauma-related DIC

Platelet transfusions are recommended in actively bleeding patients who have platelet counts below

50000mm3 (50 times 109L) and may be considered in those considered to be at high risk for bleeding (such as

DIC resulting from chemotherapy) when platelet counts fall below 10000 to 20000mm3 (10 to 20 times 109L)Plasma should be administered in bleeding patients when prothrombin timeactivated PTT exceeds 15 timesnormal or when fibrinogen levels fall below 150 milligramsdL (15 gramsL) The initial recommended doseis 15 mLkg although there is some evidence that 30 mLkg may be superior when volume overload is not ofconcern Fibrinogen concentrate should be considered when hypofibrinogenemia persists despite use ofplasma Patients with a prolonged prothrombin time should receive parenteral vitamin K

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There is no proven benefit in DIC with other coagulation factor products such as three- or four-factorprothrombin complex concentrate or recombinant factor VIIa Although there is no evidence demonstratingimproved outcomes low-molecular-weight heparin may be considered in patients with DIC wherethrombotic complications predominate the clinical picture or in patients with evidence of early compensated

DIC29 Patients with DIC are at very high risk for developing venous thromboembolism and routineprophylaxis with low-molecular-weight heparin in the absence of major bleeding is recommendedAntifibrinolytic medications (ie tranexamic acid) should generally be avoided in patients with DIC One

notable exception is in trauma-related DIC where their use reduces mortality30

CIRCULATING INHIBITORS OF COAGULATIONCIRCULATING INHIBITORS OF COAGULATION

Acquired inhibitors of blood coagulation also known as circulating anticoagulants are antibodies directedagainst one or more of the coagulation factors Although inhibitors may develop spontaneously in previouslyhealthy patients with normal hemostasis most inhibitors develop in patients with hereditary bleedingdisorders who receive transfusion of plasma products Inhibitors have been described for most of thecoagulation factors the two most common inhibitors are factor VIII inhibitors and antiphospholipidantibodies Factor VIII inhibitors are specific inhibitors directed only against factor VIII as opposed toantiphospholipid antibodies including lupus anticoagulant and anticardiolipin antibodies which arenonspecific inhibitors directed against several of the coagulation factors Lupus anticoagulant andanticardiolipin antibodies oen result in thrombosis (see chapter 234 Clotting Disorders)

Factor VIII InhibitorsFactor VIII Inhibitors

Factor VIII inhibitors most commonly develop in patients with hemophilia A (see chapter 235 Hemophiliasand von Willebrands Disease) but can also develop spontaneously in patients with previously normal

hemostasis a condition termed acquired hemophilia3132 The incidence of spontaneously arising inhibitorsis raremdashestimated at 14 cases per 1 million persons per year Although uncommon it is important torecognize this clinical entity because the mortality rate approaches 22 The majority of acquiredhemophilia cases approximately 85 occur in the elderly In about half of cases inhibitors develop inassociation with preexisting disorders such as autoimmune disorders (systemic lupus erythematosusrheumatoid arthritis ulcerative colitis) and lymphoproliferative disorders (multiple myeloma Waldenstroumlmsmacroglobulinemia benign monoclonal gammopathy of uncertain significance) and in patients with allergicdrug reactions (penicillins sulfonamides phenytoin)

Patients without a prior bleeding history who develop factor VIII inhibitors can present with massivespontaneous ecchymoses hematomas and hematuria Laboratory studies classically show a normalprothrombin time normal thrombin clotting time and a greatly prolonged activated PTT that does notcorrect with mixing A factor VIIIndashspecific assay will show very low or absent factor VIII activity Other factor-specific assays should be normal or only slightly decreased Quantitative measurement of the inhibitor bythe Bethesda inhibitor assay is important for the emergency management of bleeding episodes Long-termmanagement of acquired factor VIII inhibitors is with steroids IV immunoglobulin cytotoxic agents orLoading [Contrib]a11yaccessibility-menujs

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1

2

3

4

5

6

7

8

rituximab to suppress antibody production A hematologist should direct the management of an acuteclinically significant bleeding episode

There is no proven therapy to control bleeding episodes in patients with acquired factor VIII inhibitors33

Treatment options include administration of factor VIII three- or four-factor prothrombin complexrecombinant factor VIIa desmopressin acetate and plasmapheresis Additionally the use of aspirinnonsteroidal anti-inflammatory drugs and intramuscular injections should be avoided and conservative

therapies should be considered including compression and immobilization of the bleeding site3132

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Kenney B Stack G Drug-induced thrombocytopenia Arch Pathol Lab Med 133 309 2009 [PubMed 19195976]

Neunert C Lim W Crowther M et al The American Society of Hematology 2011 evidence-based practiceguideline for immune thrombocytopenia Blood 117 4190 2011

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Chong BH Primary immune thrombocytopenia understanding pathogenesis is the key to bettertreatments J Thromb Haemost 7 319 2009

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Sauve LJ Bettinger J Scheifele D et al Postvaccination thrombocytopenia in Canada Pediatr Infect DisJ 29 559 2010

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Despotovic JM Neunert CE Is anti-D immunoglobulin still a frontline treatment option for immunethrombocytopenia Hematology Am Soc Hematol Educ Program 2013 283 2013

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Da Rocha EC DAmico EA Caldwell SH et al A prospective study of conventional and expandedcoagulation indices in predicting ulcer bleeding aer variceal band ligation Clin Gastroenterol Hepatol 7988 2009

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Saja MF Abdo AA Sanai FM et al The coagulopathy of liver disease does vitamin K help Blood CoagulFibrinolysis 24 10 2012

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Jala DI Chonchol M Targher G Disorders of hemostasis associated with chronic kidney disease SemThromb Hemost 36 34 2010

[PubMed 20391294]

Svensson PJ Bergqvist PB Juul KV Berntorp E Desmopressin in treatment of haematological disordersand in prevention of surgical bleeding Blood Rev 28 95 2014

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Wada H Matsumoto T Yamashita Y Diagnosis and treatment of disseminated intravascular coagulation(DIC) according to four DIC guidelines J Intensive Care 2 15 2014

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Wada H Thachil J Di Nisio M et al Guidance for diagnosis and treatment of disseminated intravascularcoagulation from harmonization of the recommendations from three guidelines J Thromb Haemost 11 7612013

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Shakur H Roberts I Bautista R et al Eects of tranexamic acid on death vascular occlusive events andblood transfusion in trauma patients with significant haemorrhage (CRASH-2) a randomized placebo-controlled trial Lancet 376 23 2010

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