The syndrome of disseminated intravascular coagulation (DIC) involves a complex series of events initiated by a systemic illness (e.g., sepsis, trauma, malignancy) manifesting with thrombosis
and hemorrhage. Thrombosis is initiated by tissue factor stimu- lated thrombin activation. As antithrombin III is consumed, thrombin is left unopposed, leading to extensive intravascular fib- rin formation and organ thrombosis.
As platelets and coagulation factors are consumed, the balance shifts toward a bleeding diathesis. This includes hemorrhage into damaged tissues and ineffective thrombus formation at new sites of injury. DIC manifests clinically with hematuria, hemoptysis, oozing at mucosal surfaces, and bleeding at puncture sites.
The usual screening tests for DIC include a platelet count, PT, aPTT, fibrinogen, and D-dimer. Treatment of the instigating dis- ease process remains the only successful therapy; other measures are supportive. Platelet transfusions are indicated for platelet count <10,000-20,000/µL and cryoprecipitate transfusions for fibrino- gen levels <100 mg/dL. Heparin is used in certain clinical situa- tions, particularly when DIC is associated with acute promyelocyt- ic leukemia, but effectiveness has not been shown in clinical trials.
Book Enhancement
Go to www.acponline.org/essentials/hematology-section.html to use a table to guide the evaluation of hemophilia A and B; to distinguish between von Willebrand’s disease, hemophilia, and platelet disorders; and to view the mucocutaneous manifestations of hereditary hemorrhagic telangiectasias. In MKSAP for Students
4, assess yourself with items 14-15 in the Hematology section.
Bibliography
Drews RE.Critical issues in hematology: anemia, thrombocytopenia, coag- ulopathy, and blood product transfusions in critically ill patients. Clin Chest Med. 2003;24:607-22. [PMID: 14710693]
Bleeding Disorders • 151
Table 3. Differential Diagnosis of Prolonged Screening Coagulation Tests Not Caused by Disseminated Intravascular Coagulation
Disease Notes
Liver failure Most coagulation factors are produced in the liver. Liver failure will cause a global coagulation factor deficiency and prolongation of PT and aPTT. Platelet count is normal unless cirrhosis (with hypersplenism) is present.
Vitamin K deficiency May be due to dietary deficiency, impaired intestinal absorption, or derangement of intestinal vitamin K-producing bacterial flora. Leads to decreased levels of vitamin K-dependent coagulation factors. Mild deficiency produces prolongation of only PT; severe deficiency affects both PT and aPTT.
Massive blood loss Insufficiently compensated loss of coagulation factors may be seen in massive bleeding with transfusion of red cells without concomitant transfusion of plasma, and the laboratory picture may be difficult to differentiate from that of DIC. FDP or D-dimer levels may be normal in the early phase of trauma.
Use of unfractionated Heparin prolongs the aPTT (and only slightly the PT), whereas vitamin K-antagonists (e.g., warfarin) prolong both PT and aPTT. heparin or vitamin K Note that LMWH has no effect on aPTT. Platelet count is normal.
antagonists
Inhibiting antibody, Autoimmune disorder causing antibody-mediated destruction of a coagulation factor. Diagnosed by mixing test in which there phospholipid antibody, is lack of normalization of coagulation times after mixing patient plasma with normal plasma (1:1).
or both
152
T
he sickle mutation is a single base change (GAT →GTT) in the sixth codon of exon 1 of the β-globin gene, result- ing in replacement of the normal glutamic acid with valine at position 6 of the β-globin polypeptide. As a consequence of this single amino acid substitution, deoxygenated hemoglobin S het- erotetramers polymerize to form fibrils, causing red blood cells to sickle and hemolyze (Plate 31). Sickle cells, forming in the rel- atively hypoxic regions of tissues, impede blood flow in the microvasculature and promote vaso-occlusion, resulting in pro- found, often disabling complications, including acute pain (crises), chronic pain, and organ dysfunction or failure (Table 1). The prevalence of sickle cell trait varies widely worldwide and may be as high as 50% in certain regions, affecting individuals of African, African-American, Hispanic, Mediterranean, Asian, and Asian- Indian descent. Among persons of African ancestry, sickle cell anemia is one of the most common genetic diseases; about 10% are carriers of the sickle gene and 1:600 newborn black infants have sickle cell anemia.Screening
The goal of newborn screening is to identify infants with sickle cell anemia early and to treat them for 5 years with prophylactic penicillin (or a macrolide if there is sensitivity to penicillin), which has been shown to reduce both mortality and morbidity from pneumococcal infections in infants with sickle cell anemia and sickle-β-thalassemia. Abnormal hemoglobin may be identified in white people; most reports indicate that universal screening is more cost effective than targeted screening. For possible future primary prevention, counseling the family of the affected infant should initiate screening of other family members, especially the parents.
Diagnosis
Sickle cell anemia is inherited in an autosomal manner. If both par- ents carry sickle hemoglobin or other abnormal hemoglobin, there is a 25% risk that the fetus of each pregnancy will have sick- le cell anemia or another sickle cell syndrome. Prenatal diagnosis with therapeutic abortion is an option for preventing sickle cell anemia or other sickle cell syndromes. However, clinicians must offer family and genetic counseling to ensure that the parents fully understand the prenatal diagnosis, its complications, and possible outcome, including abortion.
Most patients with sickle cell anemia experience manifesta- tions of the disease in childhood, even as early as 6 months of age. Aspects of the medical history that support the possibility
of sickle cell anemia or a related hemoglobinopathy include recur- ring episodes of acute pain, chronic pain, and symptoms and signs of anemia and its sequelae with organ dysfunction or failure (see Table 1). The average hemoglobin level of patients with sickle cell anemia is 7-8 g/dL; the anemia is normocytic normochromic with high reticulocyte counts from stress erythropoiesis and chron- ic hemolysis. Microcytic hypochromic indices suggest sickle-β- thalassemia or co-inherited α-thalassemia. High platelet and leukocyte counts relate to asplenia due to auto-infarction.
Hemoglobin electrophoresis both at alkaline pH (cellulose acetate) and acidic pH (citrate agar) distinguishes most different structural variants of hemoglobin. High hemoglobin F levels are associated with less severe disease. Elevated hemoglobin A2levels
signify the presence of β-thalassemia. Knowledge of the molecu- lar lesion of a patient with sickle cell anemia may predict disease severity, assist family counseling and planning, and guide use of aggressive therapeutic modalities (e.g., allogeneic bone marrow transplantation).
Additional laboratory testing documents organ dysfunction caused by sickle cell anemia. Urinalysis and creatinine levels iden- tify patients with proteinuria and renal failure. In patients who have received multiple transfusions, indirect antibody testing detects alloantibodies relevant to future transfusions, while liver enzymes, viral hepatitis serologies, and serum iron chemistries identify patients who have contracted viral hepatitis and/or devel- oped iron overload. Pulmonary hypertension, correlating with older age and prior history of the acute chest syndrome, is the most common abnormality on echocardiogram with electrocar- diography demonstrating signs of right ventricular hypertrophy or strain (marked right axis deviation, tall R wave in V1, delayed
precordial transition zone with prominent S waves in leads V5
and V6, inverted T waves and ST depression in V1to V3, and
peaked P waves in lead II due to right atrial enlargement). Physical examination findings associated with sickle cell disease are sum- marized in Table 2.
Therapy
Relaxation and biofeedback methods, cognitive coping strategies, and self-hypnosis are techniques that reduce emergency depart- ment visits, hospital admissions, hospital days, and analgesic use. Goals of these interventions are to improve quality of life by increasing activity and enhancing normal function and to decrease dependence on opioid analgesics.
Supplemental oxygen should be used only in the presence of demonstrated hypoxia (pulse oximetry <92% or PaO2≤70 mm
Hg). For severe symptomatic anemia or acute organ failure,
Chapter 40
Sickle Cell Anemia
Sickle Cell Anemia • 153
blood/exchange transfusions improve blood oxygen carrying capacity and microvascular perfusion by diluting circulating sick- led erythrocytes. Exchange transfusions, a pheresis technique that removes the patient’s blood while transfusing normal, cross- matched donor blood, should be considered to decrease hemo- globin S levels <30% in managing cerebral infarcts, fat embolism, acute chest syndrome, unresponsive acute priapism, and non- healing leg ulcers. Similarly, an on-going program of exchange transfusions prevents first-time and recurrent strokes in children who are considered at high risk for developing stroke based on trans-cranial Doppler findings or have had a stroke already. To avoid increased blood viscosity, transfusions should not yield hemoglobin levels >10 g/dL. Incidence of iron overload, which
increases morbidity and mortality, is less in patients on blood exchange compared with those on simple blood transfusion. Allogeneic bone marrow transplantation (in patients <16 years of age with severe complications) may cure sickle cell anemia; its suc- cess depends on the availability of donors and the severity of the disease of the patient in question (75% -85% event-free survival, 15% graft rejection, and 10% mortality in recipients of HLA- matched donor marrow). Periodic retinal examinations are rec- ommended for monitoring and managing (photocoagulation) progressive proliferative sickle retinopathy.
Effective pain relief is best achieved with combined use of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and adjuvants (antihistamines, antidepressants, and
Table 1. Major Complications of Sickle Cell Anemia
Complication Notes
Acute chest syndrome • ACS correlates with risk of pulmonary hypertension and is the most frequent cause of death. Associated with chlamydia, (ACS) vs. pneumonia, mycoplasma, respiratory syncytial virus, coagulase-positive S. aureus, S. pneumoniae, Mycoplasma hominis, parvovirus, fat embolism, VTE and rhinovirus infections (in decreasing order of frequency).
(venous thromboembolism) • Pneumonia is usually a localized infiltration, whereas ACS is usually characterized by diffuse pulmonary infiltrates. Cultures of bronchial washings or deep sputum are usually positive in pneumonia.
• Fat embolism presents with chest pain, fever, dyspnea, hypoxia, thrombocytopenia, and multiorgan failure. Fat embolism is a component of ACS and is usually associated with acute painful episodes. It is best differentiated by the presence of fat bodies in bronchial washings or in deep sputum and by multiorgan involvement (e.g., stroke, renal failure). • Presence of lower extremity thrombophlebitis may differentiate VTE from ACS, but in some cases pulmonary arteriography may be needed. Newer contrast agents may be safer than hypertonic contrast agents, which precipitate intravascular sickling.
Avascular necrosis Involves hips and shoulders; may require surgery. More common in sickle cell-␣-thalassemia than in other sickle cell syndromes.
Cerebrovascular accidents Occurs in 8%-17% of patients. Infarction is most common in children; hemorrhage is most common in adults. Brain imaging and lumbar puncture establish the diagnosis.
Cholecystitis vs. hepatic crisis Chronic hemolysis may result in gallstones and acute cholecystitis. Fever, right upper quadrant pain, and elevated aminotransferase levels may also be due to sickle cell related ischemic hepatic crisis; abdominal ultrasonography can help differentiate.
Dactylitis vs. osteomyelitis Painful, usually symmetrical, swelling of hands or feet, erythema, and low-grade fever. More common in children before age 5. Osteomyelitis usually involves one bone.
Heart failure Related to pulmonary and systemic hypertension and ischemia. Infection Related to functional asplenia.
Leg ulcers Most common in HbS disease.
Liver disease Viral hepatitis and/or iron overload from transfusions and ischemic-induced hepatic crisis.
Pain syndrome vs. myocardial • Sickle cell pain crisis involving the chest may suggest acute MI. The quality of pain of myocardial infarction (central infarction (MI), appendicitis pressure) is different from that of sickle cell pain (sharp, pleuritic). Serial determination of cardiac enzymes will differentiate
the two.
• Abdominal pain, fever, and leukocytosis may suggest appendicitis. A high level of lactate dehydrogenase and normal bowel sounds support sickle cell pain syndrome.
Priapism Prolonged or repeated episodes may cause impotence.
Proteinuria and renal failure Prevalence of proteinuria and renal failure is approximately 25% and 5%, respectively. Pulmonary hypertension Risk of development correlates with increasing age and prior history of acute chest syndrome. Retinopathy More common in patients with compound heterozygosity for HbSC.
Sickle anemia vs. Anemia that decreases by ≥2 g/dL during a painful crisis could be due to aplastic crisis or hyperhemolysis. Aplastic crisis aplastic crisis, could be due to coexistent infection (e.g., parvovirus B19), cytotoxic drugs, or idiopathic. Hyperhemolysis could be due to hyperhemolysis infection (i.e., mycoplasma), transfusion reaction, or coexistent glucose-6-phosphate dehydrogenase deficiency.
Reticulocyte count is decreased with aplastic crisis and increased with hyperhemolysis. Bilirubin, lactic dehydrogenase, and aminotransferase levels are elevated in hyperhemolysis.
Splenomegaly and splenic Common in children aged <5 years who afterwards manifest asplenia from splenic infarction. Patients with HbSC often sequestration have splenomegaly persisting into adulthood.
anticonvulsants). Meperidine is not recommended as opioid therapy, because it is less effective than morphine or hydromor- phone and is associated with more side effects (e.g., seizures). NSAIDs should be avoided in patients with renal failure. Patients are hospitalized when severe acute painful episodes do not resolve at home with oral analgesics after 1-2 days or do not resolve or improve significantly after a minimum of 4-6 hours of treatment with parenteral opioids.
Hydroxyurea augments levels of hemoglobin F, which inhibits intracellular polymerization of hemoglobin S; it decreases the incidence of acute painful episodes by approximately 50% in responders, the incidence of acute chest syndrome, and the need for blood transfusion. Follow-up of patients taking hydrox- yurea for 9 years showed that hydroxyurea was associated with a 40% reduction in mortality. Despite its myelosuppressive effects, hydroxyurea may improve hemoglobin levels by prolonging red cell survival.
Angiotensin-converting enzyme (ACE) inhibitors prevent progressive renal disease by lowering intraglomerular pressures. Additionally, ACE inhibitors can lower protein excretion and should be used in patients with albuminuria, even in the absence of hypertension. Recombinant erythropoietin stimulates ery- thropoiesis to achieve hemoglobin levels similar to steady state val- ues (7-9 g/dL) in patients who have renal failure or to limit blood
transfusions in patients who are alloimmunized and for whom crossmatch compatible blood is difficult to find. Polyvalent (23- valent) pneumococcal polysaccharide vaccine, H. influenzae type b conjugate vaccine, and influenza vaccine prevent infections. Supplemental folic acid prevents folate deficiency (arising from chronic hemolysis) and subsequent elevation of homocystine lev- els, which may be a risk factor for stroke.
Book Enhancement
Go to www.acponline.org/essentials/hematology-section.html to view a peripheral blood smear of sickled cells, a figure show- ing dactylitis, and tables of indications for blood transfusion, hemoglobinopathy electrophoresis patterns, and commonly used tests to evaluate patients with sickle cell disease. In MKSAP
for Students 4, assess yourself with items 16 and 17 in the
Hematologysection.
Bibliography
Ballas SK.Sickle Cell Anemia. http://pier.acponline.org/physicians/diseases/ d905. [Date accessed: 2008 Jan 8] In: PIER [online database]. Philadelphia: American College of Physicians; 2008.
Frenette PS, Atweh GF.Sickle cell disease: old discoveries, new concepts, and future promise. J Clin Invest. 2007;117:850-8. [PMID: 17404610] 154 • Hematology
Table 2. Physical Examination Findings Associated with Sickle Cell Disease
Complication Notes
Fever Acute painful episodes are often associated with low-grade fever. If temperature >38.3°C (>101°F), rule out infection. Pulse Anemia, infection, and pain are often associated with tachycardia.
Respiratory rate Respiratory rate is usually 16-20/min in the steady-state. Rate <10/min suggests opioid overdose. Blood Pressure Usually low normal. Hypertension increases risk of morbidity and mortality.
Cardiac exam A systolic murmur due to anemia is common. The absence of a murmur is associated with mild anemia and no cardiomegaly. Increased intensity of the pulmonic component of S2, right-sided murmurs and gallops (increased intensity with inspiration), and prominent A wave in the jugular venous pulse are findings of pulmonary hypertension and right ventricular hypertrophy or strain. Pulmonary exam Lungs are usually clear in the steady state. Rhonchi may be heard in patients with history of recurrent ACS. Decreased breath sounds
and/or rales in a febrile patient suggest pneumonia or ACS.
Abdominal exam With age and repeated episodes of sickling, the spleen becomes small, fibrosed, and devoid of any function (autosplenectomy). However, splenomegaly may persist into young adulthood, especially in HbSC, sickle cell--thalassemia, or sickle cell-␣-thalassemia. Hepatomegaly could be a sign of iron overload or heart failure. Tender hepatomegaly suggests hepatic crisis.
Skin exam 5%-10% of patients develop leg ulcers. Most leg ulcers are located either on the medial or lateral aspect of the ankles. Neurologic exam Focal findings suggestive of stroke. Not all patients with history of stroke have residual weakness.
T
hrombocytopenia occurs through one of two mechanisms: decreased platelet production or accelerated destruction (Table 1). Most disorders that produce thrombocytopenia through inadequate bone marrow production also affect other marrow cell lines and cause additional cytopenias, which include bone marrow injury mediated by toxins (e.g., alcohol), idiosyn- cratic drug reaction, metastatic cancer, miliary tuberculosis or other infections, deficiency of vitamin B12or folic acid, and bonemarrow diseases such as acute leukemia, dysmyelopoietic syn- drome, or aplastic anemia. Accelerated peripheral platelet destruc- tion occurs in patients with splenomegaly and hypersplenism or disseminated intravascular coagulation. This chapter focuses on three other causes of accelerated platelet destruction: idiopathic
thrombocytopenic purpura (ITP), heparin-induced thrombocy- topenia (HIT), and thrombotic thrombocytopenic purpura– hemolytic uremic syndrome (TTP-HUS).