Acquired Disorders of Hemostasis

Acquired Hemorrhagic Disorders

Chapter 29 describes how the application of clinical skills forms the cornerstone for the assessment of a potential bleeding disorder. After confirming that a bleeding disorder is present through a comprehensive medical history and physical examination, the clinician should next address whether the condition is likely familial or acquired. This is sometimes difficult because some patients with mild underlying heritable hemostatic defects (e.g., mild von Willebrand disease [VWD] or platelet function defects) may not demonstrate suspicious clinical symptoms until faced with a traumatic injury or a surgical challenge at a later age. Nevertheless, acquired bleeding disorders remain a frequent clinical scenario, with presentations ranging from acute unexpected bleeding during or immediately after surgery to unusual or excessive clinical manifestations of bruising, petechiae, epistaxis, gum bleeding, or hematoma formation that occur over weeks to months. Distinguishing whether the bleeding most likely represents an abnormality in primary hemostasis, fibrin formation, or fibrinolysis provides a framework for the generation of a differential diagnosis (See Chapter 29 ). For example, petechiae are almost exclusively seen with defects in platelet number or function, whereas deep tissue hematomas are more likely associated with defects in fibrin formation, as would occur with clotting factor deficiencies. Standard screening laboratory tests such as the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are most often used in the initial evaluation but are insensitive to mild but clinically significant reductions in hemostatic capacity. In addition, a platelet count does not provide any assessment of platelet function. Therefore the clinician must rely on the history and physical findings to guide the extent of additional coagulation studies. The most common causes of acquired hemorrhagic disorders include drug-induced bleeding (e.g., anticoagulants); disseminated intravascular coagulation; liver disease; vitamin K (VK) deficiency; massive transfusion; renal disease; and, rarely, acquired inhibitors to coagulation proteins.

Drug-Induced Bleeding

Many drugs have been associated with abnormal platelet function, although not all result in bleeding manifestations. The major classes include antiinflammatory agents, antibiotics, cardiovascular drugs, psychotropic drugs, anticonvulsants, and anticoagulants. Aspirin is the commonest example, acting by irreversibly acetylating a serine residue at the active site of cyclooxygenase, whereas other nonsteroidal antiinflammatories (e.g., ibuprofen, naproxen) are reversible inhibitors. β-Lactam antibiotics can interfere with platelet function through binding to the platelet membrane. Calcium channel blockers (e.g., nifedipine) and tricyclic antidepressants, such as amitriptyline, can result in decreased platelet aggregation responses but are unlikely to result in clinical bleeding. Valproic acid has become one of the most commonly used anticonvulsants in children. Interestingly, several mechanisms of relevant valproate-induced coagulopathies have been described, including thrombocytopenia and platelet dysfunction, acquired VWD, decreased VK-dependent clotting factors, hypofibrinogenemia, and decreased factor XIII levels. Therapeutic anticoagulants (heparin, low-molecular-weight heparin, warfarin, and direct inhibitors of factor Xa and thrombin) should be the most readily apparent cause of drug-induced bleeding and in most patients can be correlated with laboratory monitoring. Platelet receptor antagonists (IIb/IIIa inhibitors; e.g., abciximab, eptifibatide, tirofiban, and adenosine diphosphate receptor antagonists; e.g., clopidogrel) are in increasing use in patients with congenital heart disease and patients undergoing interventional studies.

In most cases discontinuation of the offending drug should resolve the hemorrhagic manifestations, but this will depend on the reversibility and half-life of the drug. VK administration will in most cases rapidly reverse warfarin-induced bleeding. Alternatively, when more rapid replacement is necessary to correct low levels of factors II, VII, IX, and X, infusion with a prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) can be considered. PCCs are formulated with either three factors (II, IX, and X) or four factors (II, VII, IX, and X) and have some advantages over FFP. PCCs can be rapidly reconstituted in small infusion volumes, have a fast onset of action, do not require identification of the patient's blood group, have an exceptional safety profile with respect to risk of viral transmission owing to pathogen reduction and inactivation steps incorporated into their manufacturing, and reduced risk of adverse reactions such as transfusion-associated circulatory overload or transfusion-associated acute lung injury. A four-factor PCC, Kcentra, was recently approved by the U.S. Food and Drug Administration (FDA) for the urgent reversal of acquired coagulation factor deficiency induced by VK antagonism therapy in adults with acute major bleeding. Transfusions of fresh platelets are indicated in those patients with life-threatening or unremitting bleeding caused by drug-induced platelet dysfunction. In cases of minor bleeding in which the drug cannot be readily discontinued (e.g. anticonvulsants), desmopressin has been used with some success.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a pathologic syndrome in which the normal physiology of coagulation is disturbed by the simultaneous action of four mechanisms: increased thrombin generation, suppressed physiologic anticoagulant pathways, activation and subsequent impairment of fibrinolysis, and activation of the inflammatory pathway. This leads to widespread intravascular deposition of fibrin with resultant thrombotic end-organ complications and consumption of platelets and coagulation proteins, resulting in severe bleeding. Associated damage to the microvasculature can contribute to organ dysfunction, capillary leak, and shock.

Etiology

DIC is always a secondary phenomenon and not a disease entity in its own right. Thus its recognition should prompt the clinician to identify and treat the underlying cause rather than merely react to the bleeding manifestations. It most frequently occurs in the settings of sepsis, trauma, and systemic inflammatory syndrome, with an approximate frequency in hospitalized children of 0.4% to 1%, with sepsis accounting for approximately 95% of cases. It is primarily a clinical diagnosis based on the evaluation of laboratory results in patients with a clinical condition known to be associated with DIC ( Box 35-1 ).

Box 35-1

From Colman R, Marder V: Disseminated intravascular coagulation (DIC): pathogenesis, pathophysiology, and laboratory abnormalities. In Colman R, Marder V, Salzman E, editors: Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia, 1982, JB Lippincott, p. 654.

Causes of Disseminated Intravascular Coagulation

Infectious

Meningococcemia (purpura fulminans)
Other gram-negative bacteria (Haemophilus, Salmonella)
Gram-positive bacteria (group B Streptococcus)
Rickettsia (Rocky Mountain spotted fever)
Viruses
Malaria
Fungus

Tissue Injury

Central nervous system trauma (massive head injury)
Multiple fractures with fat emboli
Crush injury
Profound shock or asphyxia
Hypothermia or hyperthermia
Massive burns

Malignancy

Acute promyelocytic leukemia
Acute monoblastic or myelocytic leukemia
Widespread malignancies (neuroblastoma)

Venom or Toxin

Snake bites
Insect bites

Microangiopathic Disorders

“Severe” thrombotic thrombocytopenic purpura
Hemolytic-uremic syndrome
Giant hemangioma (Kasabach-Merritt syndrome)

Gastrointestinal Disorders

Fulminant hepatitis
Severe inflammatory bowel disease
Reye syndrome

Hereditary Thrombotic Disorders

Homozygous protein C deficiency

Miscellaneous

Severe graft rejection
Acute hemolytic transfusion reaction
Severe collagen-vascular disease
Kawasaki disease
Heparin-induced thrombosis
Infusion of “activated” prothrombin complex concentrates
Hyperpyrexia/encephalopathy, hemorrhagic shock syndrome

Clinical Presentation

The clinical manifestations of DIC include bleeding, thrombosis, or both, however typically bleeding predominates. Early indicators are bleeding resulting from venipunctures, intravascular accesses, and surgical wounds. Mucocutaneous bleeding may manifest as bruising, petechiae, epistaxis, gum bleeding, blood from tracheal aspirates, gastrointestinal bleeding, and hematuria. In fulminant cases it may lead to bleeding into vital organs. However, with increasingly sensitive diagnostic tests that can detect endogenous activation of the hemostatic process, the clinical spectrum of DIC is broad. Nonovert DIC describes a stressed but compensated hemostatic system, in which the laboratory tests are abnormal but there are no clinical manifestations. Overt DIC is described as a stressed and decompensated hemostatic system, in which the laboratory tests are abnormal and clinical bleeding or microvascular thrombosis and organ dysfunction exists. Overt DIC may be controlled or uncontrolled depending on whether the process will resolve when the underlying stimulus is removed.

Diagnosis

The clinical presentation of a profoundly ill child with bleeding believed to be secondary to DIC can be supported by laboratory tests showing evidence of a consumptive coagulopathy with activation of the fibrinolytic cascade. Moderate to severe thrombocytopenia with or without anemia will be evident from the complete blood count. Thrombocytopenia is present in approximately 50% of patients and suggests consumption of platelets. Anemia could be caused by bleeding or, when accompanied by schistocytes on blood smear, evidence of microangiopathic hemolytic anemia. The PT and aPTT are prolonged in 50% to 60% of patients, reflecting consumption of many coagulation proteins, including prothrombin; factors V, VII, and VIII; and fibrinogen. Fibrinogen or fibrin degradation products (FDPs) and D-dimers are both increased in concentration in most patients with DIC, suggesting activation of the fibrinolytic process. Marked reductions in plasma anticoagulants including proteins C and S and antithrombin (AT) have also been described. The most sensitive tests for diagnosis of DIC are markers of endogenous thrombin generation: prothrombin fragment 1.2 and thrombin-AT (TAT) complexes. Prothrombin fragment 1.2 is released when thrombin is generated from prothrombin. TAT complexes are generated by binding of thrombin with its inhibitor AT. The standard assays (PT, aPTT, platelet count, and D-dimers) are relatively rapid and simple to perform. However, changes in these test results do not always occur at the same time, and laboratory values change rapidly depending on the patient's clinical status. This may create confusion in patient management and make the diagnosis of DIC at an early stage particularly difficult. The International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring system for overt DIC has been widely used in intensive care units, and several publications have validated the score against morbidity scores. The five-step algorithm assigns a score based on the severity of abnormality for each of the following: platelet count (>100 × 109/L = 0; <100 × 109/L = 1; <50 × 109/L = 2), elevated fibrin-related markers (no increase = 0; moderate increase = 2; strong increase = 3), prolonged prothrombin time (<3 seconds = 0; <3 seconds but <6 seconds = 1; >6 seconds = 2), and fibrinogen level (>1 g/L =0; <1 g/L = 1). A total score of 5 or more is considered compatible with overt DIC. The sensitivity and specificity of this scoring system are greater than 90%. However, the algorithm should be applied only in the presence of an underlying disorder known to be associated with DIC. Despite its use in many pediatric intensive care units in the United States, there remains a paucity of clinical research studies examing the utility of the ISTH scoring system in children. Investigators at Texas Children's Hospital have compared their institutional modified DIC criteria with the ISTH diagnostic score against a gold-standard diagnostic method of confirmation of DIC in a subset of children who died. Their modified criteria is not a scoring system but a sequential analysis of coagulation assays (PT, platelet count, fibrinogen, and D-dimer) as evaluated by transfusion medicine specialists along with the patient's clinical condition. Such an approach yielded a higher sensitivity, owing to the inclusion of sequential testing, to recognize a trend in the evolution from an early-phase DIC to overt DIC.

Treatment

The fundamental principal of DIC treatment is the specific and vigorous treatment of the underlying disorder. In some cases DIC will completely resolve within hours after resolution of the underlying condition (e.g., appropriate control of sepsis with antimicrobials). However, in other cases supportive measures are required to control the DIC until the underlying condition is resolved (e.g., the use of all- trans -retinoic acid and chemotherapy for the treatment of acute promyelocytic leukemia and DIC. ) Therapeutic interventions remain controversial and must be individualized according to the underlying basis for the DIC and severity of the clinical symptoms. For example, in nonovert DIC, children do not usually require therapy for the DIC itself. However, in the presence of uncontrolled overt DIC, therapeutic intervention including blood replacement products may be indicated to improve hemostasis while waiting for effective therapy for the underlying condition. Treatment modalities investigated include blood component therapy, anticoagulants, restoration of natural anticoagulant pathways, and other agents.

Blood Component Therapy.

In general, the more severe the laboratory abnormalities, in particular the degree of thrombocytopenia and coagulation factor depletion, the greater the risk of bleeding complications with DIC. Hence treatment with FFP, fibrinogen, cryoprecipitate, and platelets appears to be a rational therapy in bleeding patients or patients who are at risk for bleeding with a significant depletion of these hemostatic factors. However, blood component therapy should not be instituted on the basis of laboratory results alone; it is indicated only in patients with active bleeding, those who require an invasive procedure, or those who are otherwise at risk for bleeding complications. Large volumes of plasma (15 to 30 mL/kg) may be necessary to correct the coagulation defect. PCC may be considered in actively bleeding patients if FFP transfusion is not possible. However, these products lack certain essential coagulation factors, such as factor V. The efficacy and safety of recombinant factor VIIa in DIC with life-threatening bleeding are unknown. Reasonable goals are to maintain platelet counts above 50 × 10 ⁹ /L, fibrinogen concentrations above 1.5 g/L, and PT values less than double the normal range.

Anticoagulant Therapy.

Considering the central role played by thrombin in DIC, the use of heparin or other anticoagulants to inhibit thrombin generation appears reasonable. Heparin can at least partly inhibit the activation of coagulation in sepsis and other causes of DIC. However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has never been demonstrated in controlled clinical trials and is not a standard of care in overt cases of DIC. However, therapeutic doses of heparin may be indicated in patients with clinically overt thromboembolism, chronic DIC, or extensive fibrin deposition such as seen in purpura fulminans or acral ischemia.

Replacement of Natural Anticoagulant.

Depleted levels of AT, protein C, and protein S cannot be effectively replaced with FFP alone because of the short plasma half-life of these proteins. AT and protein C concentrates have been extensively evaluated in patients with DIC. Trials of AT therapy have not yet provided conclusive evidence sufficient to make treatment recommendations. The double-blind, placebo-controlled, phase III trial of recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) demonstrated a significant decrease in mortality for the protein C–treated group compared with placebo. However, these findings were not replicated in later trials, treatment was associated with a higher risk of bleeding, and recombinant human protein C was ultimately withdrawn in 2011. Soluble recombinant human thrombomodulin acts by reducing thrombin-mediated clotting, enhancing protein C activation at the site of clotting, as well as demonstrating some antiinflammatory properties. However, a large randomized controlled trial failed to demonstrate a benefit in 28-day mortality rates.

Other Agents.

Recently, recombinant factor VIIa (rVIIa) has become an attractive strategy to control bleeding in various scenarios. In situations where volume overload is an issue or bleeding persists despite adequate blood component support, use of rVIIa has been shown to be effective. However, these data have mostly been generated from anecdotal reports, and given the potential adverse thrombotic complications with this agent, controlled randomized trials are required to address its safety and efficacy in these patients. Antifibrinolytic agents can be effective in bleeding patients, but the use of these agents in patients with bleeding associated with DIC is generally not recommended. They could be considered in cases when hyperfibrinolysis is suspected, such as may occur with acute promyelocytic leukemia or trauma.

Liver Disease

Pathophysiology

The liver is the main site of synthesis for most hemostatic components. However, the hemostatic impairment in liver disease involves a variety of mechanisms, including impaired hepatic synthesis, activation of the coagulation and fibrinolytic systems, poor clearance of activated hemostatic components, loss of hemostatic proteins into ascitic fluid, concurrent VK deficiency, thrombocytopenia, and impaired platelet function. When both procoagulants and anticoagulants are reduced, hemostatic dysregulation results in both a propensity to hemorrhage and a propensity to thrombose. Along with reduced synthesis there may be secretion of abnormal forms of the hemostatic proteins that may function as inhibitors to coagulation. For example, abnormal fibrinogens (dysfibrinogenemias) are very common in liver disease. Similarly, VK-dependent proteins (factors II, VII, IX, X, protein C, protein S, and protein Z) decrease in liver disease. However, they may also be secreted in forms with abnormal gamma-carboxylation reactions of the glutamic acid residues on the amino-terminal portion of the protein leading to reduced functional activity. Hypofibrinogenemia may be related to decreased synthesis, or increased consumption (e.g., DIC). However, in patients with acute liver failure, plasminogen activator inhibitor (PAI-1) is increased, shifting the balance toward hypofibrinolysis. This occurs despite elevated levels of tissue plasminogen activator (tPA) that may be secondary to increased release from the activated endothelium or reduced clearance by the diseased liver (or both). The other proteins involved in fibrinolysis (plasminogen, α2-antiplasmin, thrombin activatable fibrinolysis inhibitor, and factor XIII) are typically reduced because of decreased liver synthesis. In addition, several structural manifestations of liver disease can contribute to the bleeding in these patients, including portal hypertension, varices, gastritis, and hemorrhoids.

Clinical Presentation

Clinical symptoms are variable and dependent, to some extent, on the etiology of the liver failure and associated invasive procedures. Symptoms include ecchymosis and petechiae, mucous membrane bleeding, hemorrhage from gastrointestinal varices, and hemorrhage into the abdomen or central nervous system (CNS). However, clinically significant bleeding occurs rarely in acute liver failure (approximately 5% to 10% of cases). Coagulation screening tests (aPTT, PT, thrombin clotting time) are usually prolonged, platelet counts are reduced, and bleeding time is prolonged. Plasma concentrations of FVII; FV; and, less commonly, fibrinogen are decreased. Levels of FVIII may be normal or elevated, possibly reflecting reduced clearance via low-density-lipoprotein receptor-related protein, and can be helpful in distinguishing severe liver disease from DIC. However, both conditions may occur simultaneously. FDPs or D-dimer levels are often increased in hepatic failure and contribute to prolongation of the thrombin clotting time and impaired platelet function. Dysfibrinogenemia will contribute to prolongations of the PT and aPTT, but the thrombin time and reptilase assays are more sensitive. Dysfibrinogenemia may be confirmed by demonstrating an abnormal ratio of clottable fibrinogen (functional assay) to fibrinogen antigen (immunoassay).

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