THE MAIN HAEMATOLOGICAL SYNDROMES
Anemia may be defined as any condition resulting from a significant decrease in the total body erythrocyte mass. Measurement of total body rbc mass requires special radiolabeling techniques that are not amenable to general medical diagnostic work. Measurements typically substituted for rbc mass determination take advantage of the body's tendency to maintain normal total blood volume by dilution of the depleted rbc component with plasma. This adjustment results in decrease of the total blood hemoglobin concentration, the rbc count, and the hematocrit. Therefore, a pragmatic definition of anemia is a state which exists when the hemoglobin is less than 12 g/dL or the hematocrit is less than 37 cL/L. Anemia may exist as a laboratory finding in a subjectively healthy individual, because the body can, within limits, compensate for the decreased red cell mass.
One must be careful in blindly applying this practical definition of anemia in every case. As the following diagram shows, it is possible to be severely anemic and have a normal hematocrit (and hemoglobin). This occurs when there is rapid hemorrhage, with red cells and plasma being rapidly lost simultaneously, before the body can respond by hiking up the plasma volume.
The final example in the above diagram illustrates that a person can have a low hematocrit and not be anemic. This occurs when a patient is overhydrated, typically as a result of overenthusiastic intravenous fluid therapy.
Clinical signs and symptoms of anemia
When the above mechanisms are overwhelmed by the increasing magnitude of the anemia, or when the demands of physical activity or intercurrent illness overwhelm them, a clinical disease state becomes apparent to the physician and to the patient. The severity of clinical symptoms bears less relationship to the severity of the anemia than to the length of time over which the condition develops. An acute hemorrhagic condition may produce symptoms with loss of as little as 20% of the total blood volume (or 20% of the total red cell mass). Conversely, anemias developing over periods long enough to allow compensatory mechanisms to operate will allow much greater loss of rbc mass before producing symptoms. It is not terribly uncommon to see a patient with a hemoglobin of 4 g/dL (hematocrit 12 cL/L), representing a loss of 70% of the rbc mass, being reluctantly dragged into a clinic by relatives concerned that he or she is looking a bit washed out.
When symptoms do develop, they are pretty much what you would expect given the precarious state of oxygen delivery to the tissues: dyspnea on exertion, easy fatigability, fainting, lightheadedness, tinnitus, and headache. In addition, the hyperdynamic state of the circulatory system can produce palpitations and roaring in the ears. Pre-existing cardiovascular pathologic conditions are, as you would expect, exacerbated by the anemia. Angina pectoris, intermittent claudication, and night muscle cramps speak to the effect of anemia on already compromised perfusion.
Clinical signs of a slowly developed anemia are pallor, tachycardia, and a systolic ejection murmur. In rapidly developing anemia (as from hemorrhage and certain catastrophic hemolytic anemias), additional symptoms and signs are noted: syncope on rising from bed, orthostatic hypotension (i.e., the blood pressure falls when the patient is raised from the supine to the sitting or standing positions) and orthostatic tachycardia. Keep in mind that if anemia develops through rapid enough bleeding, the hematocrit and hemoglobin will be normal (since in hemorrhage the rbc's and plasma are lost in proportion). Because of this, your appreciation of these clinical signs will serve you better in diagnosing this type of anemia than will the laboratory.
Classification of anemias
Anemias can be classified by cytometric schemes (i.e., those that depend on cell size and hemoglobin-content parameters, such as MCV and MCHC), erythrokinetic schemes (those that take into account the rates of rbc production and destruction), and biochemical/molecular schemes (those that consider the etiology of the anemia at the molecular level.
An example: sickle cell anemia
- Cytometric classification: normochromic, normocytic
- Erythrokinetic classification: hemolytic
- Biochemical/molecular classification: DNA point mutation producing amino acid substitution in hemoglobin beta chain
A. Cytometric classification
Because cytometric parameters are more easily and less expensively measured than are erythrokinetic and biochemical ones, it is most practical to work from the cytometric classification, to the erythrokinetic, and then (hopefully) to the biochemical. Your first job in working up a patient with anemia is to place the case in one of three major cytometric categories:
1. Normochromic, normocytic anemia (normal MCHC, normal MCV).
1. anemias of chronic disease
2. hemolytic anemias (those characterized by accelerated destruction of rbc's)
3. anemia of acute hemorrhage
4. aplastic anemias (those characterized by disappearance of rbc precursors from the marrow)
2. Hypochromic, microcytic anemia (low MCHC, low MCV).
1. iron deficiency anemia
3. anemia of chronic disease (rare cases)
3. Normochromic, macrocytic anemia (normal MCHC, high MCV).
1. vitamin B12 deficiency
2. folate deficiency
B. Erythrokinetic classification
You would now want to proceed with classifying your case based on the rate of rbc turnover. If this is high, a normoregenerative anemia exists. Such anemias are seen in hemolysis (excess destruction of rbc's) or hemorrhage (loss of rbc's from the vascular compartment. In these cases, the marrow responds appropriately to anemia by briskly stepping up the production of rbc's and releasing them into the bloodstream prematurely. There are several lab tests that allow you to determine if increased rbc turnover exists:
1. Reticulocyte count
A sample of blood is stained with a supravital dye that marks reticulocytes. An increased number of reticulocytes is seen when the marrow is churning out rbc's at excessive speed (presumably to make up for those lost to hemolysis or hemorrhage). Most labs will report the result of the reticulocyte count in percent of all rbc's counted. A typical normal range is 0.5-1.5 %. Making clinical decisions based on this raw count is somewhat fallacious.
For instance: A normal person with an rbc count of 5,000,000 /microliter and an absolute reticulocyte count of 50,000 /microliter would have a relative retic count of 1.0%. An anemic person with 2,000,000 rbc's/microliter and the same 50,000 retics/microliter would have an apparently "abnormal" relative retic count of 2.5 % and could be misdiagnosed as having high turnover.
Clearly, one needs to find some way to correct the raw retic count so as to avoid this problem. One can easily calculate the absolute retic count (in cells/microliter) by multiplying the rbc count by the relative retic count. The normal range for the absolute retic count is 50,000-90,000 /microliter.
2. Bone marrow biopsy
This can be used to directly observe any accelerated production of rbc's. The ratio of the number of myeloid to erythroid precursors (the M:E ratio) tends to decrease in high-production states, and the marrow becomes hypercellular. Marrow biopsy is not usually performed just to measure the M:E ratio, but to answer other hematologic questions that have been raised.
The normoregenerative anemias are in contrast to those characterized by inadequate marrow response to the degree of anemia. These are the hyporegenerative anemias. In such cases, the reticulocyte production index is decreased. The classic example is aplastic anemia, in which there is primary marrow failure to produce enough erythrocyte mass. As you have probably come to expect, the distinction of these categories is not always absolute. For instance, in thalassemia major there is a degree of hemolysis (generally associated with the normoregenerative states) and inadequate marrow response to the degree of anemia.
C. Biochemical classification
Finally, one should attempt to determine the etiology of the anemia as specifically as possible. In some cases (e.g., iron deficiency), etiologic classification is easily attained; in others (e.g.. aplastic anemia) the biochemical mechanism of disease may be hopelessly elusive. Generally, biochemical tests are aimed at identifying a depleted cofactor necessary for normal hematopoiesis (iron, ferritin, folate, B12), an abnormally functioning enzyme (glucose-6-phosphate dehydrogenase, pyruvate kinase), or abnormal function of the immune system (the direct antiglobulin [Coombs'] test).
Myelodysplastic syndromes (MDS)
The myelodysplastic syndromes (MDS, formerly known as "preleukemia") are a diverse collection of hematological (blood-related) medical conditions that involve ineffective production (or dysplasia) of the myeloid class of blood cells.
Patients with MDS often develop severe anemia and require frequent blood transfusions. In most cases, the disease worsens and the patient develops cytopenias (low blood counts) due to progressive bone marrow failure. In about one third of patients with MDS, the disease transforms into acute myelogenous leukemia (AML), usually within months to a few years.
The myelodysplastic syndromes are all disorders of the stem cell in the bone marrow. In MDS, hematopoiesis (blood production) is disorderly and ineffective. The number and quality of blood-forming cells decline irreversibly, further impairing blood production.
French-American-British (FAB) classification
In 1974 and
Refractory anemia (RA)
characterized by less than 5% primitive blood cells (myeloblasts) in the bone marrow and pathological abnormalities primarily seen in red cell precursors
also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts"
characterized by 5-20% myeloblasts in the marrow
Refractory anemia with excess blasts in transformation (RAEB-T)
characterized by 21-30% myeloblasts in the marrow (>30% blasts is defined as acute myeloid leukemia)
Chronic myelomonocytic leukemia (CMML), not to be confused with chronic myelogenous leukemia or CML
characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 109/uL monocytes (a type of white blood cell) circulating in the peripheral blood.
A table comparing these is available from the Cleveland Clinic
The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of three to five years, although long-term remission is possible if a bone marrow transplant is successful). The worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. About one quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated disease. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997. This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.
The FAB classification was used by pathologists and clinicians for almost 20 years.
World Health Organization
In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. Most recently the WHO has evolved a new classification scheme (2008) which is based more on genetic findings. However, morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy is still the screening test used in order to decide which classification is best and which cytogenetic aberrations may be related.
The list of dysplastic syndromes under the new WHO system includes:
Refractory anemia (RA)
Refractory cytopenia with unilineage dysplasia (Refractory anemia, Refractory neutropenia, and Refractory thrombocytopenia)
anemia with ring sideroblasts (RARS)
Refractory cytopenia with multilineage dysplasia (RCMD) includes the subset Refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). RCMD includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia.
Refractory anemia with excess blasts I and II. RAEB was divided into *RAEB-I (5-9% blasts) and RAEB-II (10-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia.
Refractory anemia with excess blasts in transformation (RAEB-T)
category of RAEB-T was eliminated; such patients are now considered to have
acute leukemia. 5q- syndrome, typically seen in older women with normal or
high platelet counts and isolated deletions of the long arm of chromosome
CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes.
Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)
Refractory cytopenia of childhood (dysplasia in childhood) - New WHO classification 2008
Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.
The median age at diagnosis of a MDS is between 60 and 75 years; a few patients are younger than 50; MDS diagnoses are rare in children. Males are slightly more commonly affected than females. Signs and symptoms are nonspecific and generally related to the blood cytopenias:
§ Anemia—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
§ Neutropenia (low neutrophil count) —increased susceptibility to infection
§ Thrombocytopenia (low platelet count) —increased susceptibility to bleeding and ecchymosis (bruising), as well as subcutaneoushemorrhaging resulting in purpura or petechia
Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:
§ neutropenia, anemia and thrombocytopenia (low cell counts of white and red blood cells, and platelets, respectively);
§ splenomegaly or rarely hepatomegaly;
§ abnormal granules in cells, abnormal nuclear shape and size; and/or
§ chromosomal abnormalities, including chromosomal translocations and abnormal chromosome number.
MDS must be differentiated from anemia, thrombocytopenia, and/or leukopenia. Usually, the elimination of other causes of these cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.
A typical investigation includes:
§ Full blood count and examination of blood film. The blood film morphology can provide clues about hemolytic anemia, clumping of theplatelets leading to spurious thrombocytopenia, or leukemia.
§ Blood tests to eliminate other common causes of cytopenias, such as lupus, hepatitis, B12, folate, or other vitamin deficiencies, renal failure or heart failure, HIV, hemolytic anemia, monoclonal gammopathy. Age-appropriate cancer screening should be considered for allanemic patients.
§ Bone marrow examination by a hematopathologist. This is required to establish the diagnosis, since all hematopathologists consider dysplastic marrow the key feature of myelodysplasia.
§ Cytogenetics or chromosomal studies. This is ideally performed on the bone marrow aspirate. Conventional cytogenetics requires a fresh specimen, since live cells are induced to enter metaphase to enhance chromosomal staining. Alternatively, virtual karyotyping can be done for MDS, which uses computational tools to construct the karyogram from disrupted DNA. Virtual karyotyping does not require cell culture and has dramatically higher resolution than conventional cytogenetics, but cannot detect balanced translocations.
§ Flow cytometry is helpful to establish the presence of any lymphoproliferative disorder in the marrow.
Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important historic fact. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process. Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia.
The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Males are slightly more frequently affected than females. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam veterans that were exposed to Agent Orange are at risk of developing MDS.
The features generally used to define a MDS are: blood cytopenias; ineffective hematopoiesis; dyserythropoiesis; dysgranulopoiesis; dysmegakaropoiesis and increased myeloblast.
Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
§ Granulocytic series
1. Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
2. Hyposegmented neutrophils (Pseudo-Pelger Huet)
3. Hypogranular neutrophils or pseudo Chediak Higashi large granules
4. Auer rods - automatically RAEB II (if blast count <5% in the peripheral blood and <10% in the bone marrow aspirate) also note Auer rods may be seen in mature neutrophils in AML with translocation t(8;21)
5. Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
§ Erythroid series
1. Binucleated erythroid percursors and karyorrhexis
2. Erythroid nuclear budding
3. Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
4. Loss of E-cadherin in normoblasts is a sign of aberrancy
5. PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
6. Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
§ Megakaryocytic series (can be the most subjective)
1. Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
2. Hypersegmented (osteoclastic appearing) megakaryocytes
3. Ballooning of the platelets (seen with interference contrast microscopy)
Myeloproliferative Syndrome (Chronic Myeloproliferative Disorders, CMPD)
The chronic myeloproliferative disorders (previously also called the myeloproliferative syndromes) include chronic myeloid leukemia (CML), osteomyelosclerosis (OMS), polycythemia vera (PV) and essential thrombocythemia (ET). Clearly, noxious agents of unknown etiology affect the progenitor cells at different stages of differentiation and trigger chronic malignant proliferation in the white cell series (CML), the red cell series (PV), and the thrombocyte series (ET). Sometimes, they lead to concomitant synthesis of fibers (OMS). Transitional forms and mixed forms exist particularly between PV, ET, and OMS.
The chronic myeloproliferative disorders
encompass chronic autonomous disorders of the bone marrow and the embryonic
blood-generating organs (spleen and liver), which may involve one or several cell
lines. The common attributes of these diseases are onset in middle age,
development of splenomegaly, and slow disease
progression (Table 20). In 95% of cases, CML shows a specific
chromosome aberration (
Definition of the “hemorrhagic syndrome“ and “hemorrhagic diathesis.”
Bleeding from a platelet disorder is usually localized to superficial sites such as the skin and mucous membranes, comes on immediately after trauma or surgery, and is readily controlled by local measures. In contrast, bleeding from secondary hemostatic or plasma coagulation defects occurs hours or days after injury and is unaffected by local therapy. Such bleeding most often occurs in deep subcutaneous tissues, muscles, joints, or body cavities. A careful and thorough history may establish the presence of a hemostatic disorder and guide initial laboratory testing.
Hemorrhagic spots on surface of the skin, patechiae, purpura, heleangiectasis, and hemorrhages. These signs are present not only on the skin, but in subcutaneous fat, muscle, brain too. The hemorrhagic syndrome is usual in case of inherited thrombocytopenic purpuras, neonatal thrombocytopenic purpuras. The other signs of this syndrome are bleeding, hematuria, upper and lower gastrointestinal tract hemorrhage, prolonged bleeding from the umbilical stump or from veni-punctures, intracranial hemorrhage.
Platelets arise from the fragmentation of megakaryocytes, which are very large, polyploid bone marrow cells produced by the process of endomitosis. They undergo from three to five cycles of chromosomal duplication without cytoplasmic division. After leaving the marrow space, about one-third of the platelets are sequestered in the spleen, while the other two-thirds circulate for 7 to 10 days. Normally, only a small fraction of the platelet mass is consumed in the process of hemostasis, so most platelets circulate until they become senescent and are removed by phagocytic cells. The normal blood platelet count is 150,000 to 450,000/ul. A decrease in platelet count stimulates an increase in the number, size, and ploidy of megakaryocytes, releasing additional platelets into the circulation. This process is regulated by thrombopoietin (TPO) binding to its megakaryocyte receptor, a proto-oncogene c-mpl. TPO (c-mpl ligand) is secreted continuously at a low level and binds tightly to circulating platelets. A reduction in platelet count increases the level of free TPO and thereby stimulates megakaryocyte and platelet production.
The platelet count varies during the menstrual cycle, rising following ovulation and falling at the onset of menses. It is also influenced by the patient's nutritional state and can be decreased in severe iron, folic acid, or vitamin B12 deficiency. Platelets are acute-phase reactants, and patients with systemic inflammation, tumors, bleeding, and mild iron deficiency may have an increased platelet count, a benign condition called secondary or reactive thrombocytosis. The cytokines interleukin (IL)-3, IL-6, and IL-11 may stimulate platelet production in acute inflammation. In contrast, the increase in platelet count that is characteristic of the myeloproliferative disorders such as polycythemia vera, chronic myelogenous leukemia, myeloid metaplasia, and essential thrombocytosis can cause either severe bleeding or thrombosis. In these patients, unregulated platelet production is secondary to a clonal stem cell abnormality affecting all the bone marrow progenitors.
Thrombocytopenia is caused by one of three mechanisms-decreased bone marrow production, increased splenic sequestration, or accelerated destruction of platelets. In order to determine the etiology of thrombocytopenia, each patient should have a careful examination of the peripheral blood film, an assessment of marrow morphology by examination of an aspirate or biopsy, and an estimate of splenic size by bedside palpation supplemented, if necessary, by ultrasonography or computed tomographic (CT) scan. Occasional patients have "pseudothrombocytopenia," a benign condition in which platelets agglutinate or adhere to leukocytes when blood is collected with EDTA as anticoagulant. This is a laboratory artifact, and the actual platelet count in vivo is normal.
Impaired Production Disorders that injure stem cells or prevent their proliferation frequently cause thrombocytopenia. They usually affect multiple hematopoietic cell lines so that thrombocytopenia is accompanied by varying degrees of anemia and leukopenia. Diagnosis of a platelet production defect is readily established by examination of a bone marrow aspirate or biopsy, which should show a reduced number of megakaryocytes. The most common causes of decreased platelet production are marrow aplasia, fibrosis, or infiltration with malignant cells, all of which produce highly characteristic marrow abnormalities. Occasionally, thrombocytopenia is the presenting laboratory abnormality in these disorders. Cytotoxic drugs impair megakaryocyte proliferation and maturation and frequently cause thrombocytopenia. Rare marrow disorders such as congenital amegakaryocytic hypoplasia and thrombocytopenia with absent radii (TAR syndrome), produce a selective decrease in megakaryocyte production.
Splenic Sequestration Since one-third of the platelet mass is normally sequestered in the spleen, splenectomy will increase the platelet count by 30%. Postsplenectomy thrombocytosis is a benign self-limited condition that does not require specific therapy. In contrast, when the spleen enlarges, the fraction of sequestered platelets increases, lowering the platelet count. The most common causes of splenomegaly are portal hypertension secondary to liver disease and splenic infiltration with tumor cells in myeloproliferative or lymphoproliferative disorders. Isolated splenomegaly is rare, and in most patients it is accompanied by other clinical manifestations of an underlying disease. Many patients with leukemia, lymphoma, or a myeloproliferative syndrome have both marrow infiltration and splenomegaly and develop thrombocytopenia from a combination of impaired marrow production and splenic sequestration of platelets.
Accelerated Destruction Abnormal vessels, fibrin thrombi, and intravascular prostheses can all shorten platelet survival and cause nonimmunologic thrombocytopenia. Thrombocytopenia is common in patients with vasculitis, the hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), or as a manifestation of disseminated intravascular coagulation (DIC). In addition, platelets coated with antibody, immune complexes, or complement are rapidly cleared by mononuclear phagocytes in the spleen or other tissues, inducing immunologic thrombocytopenia. The most common causes of immunologic thrombocytopenia are viral or bacterial infections, drugs, and a chronic autoimmune disorder referred to as idiopathic thrombocytopenic purpura (ITP). Patients with immunologic thrombocytopenia do not usually have splenomegaly and have an increased number of bone marrow megakaryocytes.
Many common drugs can cause thrombocytopenia. Cancer chemotherapeutic agents may depress megakaryocyte production. Ingestion of large quantities of alcohol has a marrow-depressing effect leading to transient thrombocytopenia, particularly in binge drinkers. Thiazide diuretics, used to treat hypertension or congestive heart failure, impair megakaryocyte production and can produce mild thrombocytopenia (50,000 to 100,000/uL), which may persist for several months after the drug is discontinued.
Most drugs induce thrombocytopenia by eliciting an immune response in which the platelet is an innocent bystander. The platelet is damaged by complement activation following the formation of drug-antibody complexes. Current laboratory tests can identify the causative agent in 10% of patients with clinical evidence of drug-induced thrombocytopenia. The best proof of a drug-induced etiology is a prompt rise in the platelet count when the suspected drug is discontinued. Patients with drug-induced platelet destruction may also have a secondary increase in megakaryocyte number without other marrow abnormalities.
Although most patients recover within 7 to 10 days and do not require therapy, occasional patients with platelet counts <10,000 to 20,000/uL have severe hemorrhage and may require temporary support with glucocorticoids, plasmapheresis, or platelet transfusions while waiting for the platelet count to rise. A patient who has recovered from drug-induced immunologic thrombocytopenia should be instructed to avoid the offending drug in the future, since only minute amounts of drug are needed to set up subsequent immune reactions. Certain drugs that are cleared from body storage depots quite slowly, such as phenytoin, may induce prolonged thrombocytopenia.
Heparin is a common cause of thrombocytopenia in hospitalized patients. Between 10 and 15% of patients receiving therapeutic doses of heparin develop thrombocytopenia and, occasionally, may have severe bleeding or intravascular platelet aggregation and paradoxical thrombosis. Heparin-induced thrombosis, sometimes called the "white clot syndrome," can be fatal unless recognized promptly. Most cases of heparin thrombocytopenia are due to drug-antibody binding to platelets; some are secondary to direct platelet agglutination by heparin. The offending antigen is a complex formed between heparin and the platelet-derived heparin neutralizing protein, platelet factor 4. Prompt cessation of heparin will reverse both thrombocytopenia and heparin-induced thrombosis. Low-molecular-weight heparin products have reduced the incidence of heparin-induced thrombocytopenia. They are effective antithrombotic agents and are less immunogenic. Unfortunately, 80 to 90% of the antibodies generated against conventional heparins cross-react with low-molecular-weight heparins, so only a minority of patients with preformed antibody can be treated with this product.
IDIOPATHIC THROMBOCYTOPENIC PURPURA
The immunologic thrombocytopenias can be classified on the basis of the pathologic mechanism, the inciting agent, or the duration of the illness. The explosive onset of severe thrombocytopenia following recovery from a viral exanthem or upper respiratory illness (acute ITP) is common in children and accounts for 90% of the pediatric cases of immunologic thrombocytopenia. Of these patients, 60% recover in 4 to 6 weeks and >90% recover within 3 to 6 months. Transient immunologic thrombocytopenia also complicates some cases of infectious mononucleosis, acute toxoplasmosis, or cytomegalovirus infection and can be part of the prodromal phase of viral hepatitis and initial infection with HIV. Acute ITP is rare in adults and accounts for <10% of postpubertal patients with immune thrombocytopenia. Acute ITP is caused by immune complexes containing viral antigens that bind to platelet Fc receptors or by antibodies produced against viral antigens that cross-react with the platelet. In addition to these viral disorders, the differential diagnosis includes atypical presentations of aplastic anemia, acute leukemias, or metastatic tumor. A bone marrow examination is essential to exclude these disorders, which can occasionally mimic acute ITP.
Most adults present with a more indolent form of thrombocytopenia that may persist for many years and is referred to as chronic ITP. Women age 20 to 40 are afflicted most commonly and outnumber men by a ratio of 3:1. They may present with an abrupt fall in platelet count and bleeding similar to patients with acute ITP. More often they have a prior history of easy bruising or menometrorrhagia. These patients have an autoimmune disorder with antibodies directed against target antigens on the glycoprotein IIb-IIIa or glycoprotein Ib-IX complex. Although most antibodies function as opsonins and accelerate platelet clearance by phagocytic cells, occasional antibodies bind to epitopes on critical regions of these glycoproteins and impair platelet function. Platelet-associated IgG can be measured but specificity is a problem. High "background" level of IgG on normal platelets and elevations in plasma immunoglobulin levels or in circulating immune complexes will nonspecifically increase platelet-associated IgG. Few clinical situations require platelet-associated IgG testing.
A low platelet count may be the initial manifestation of systemic lupus erythematosus (SLE) or the first sign of a primary hematologic disorder. Thus, patients with chronic ITP should have a bone marrow examination and an antinuclear antibody determination. In addition, patients with hepatic or splenic enlargement, lymphadenopathy, or atypical lymphocytes should have serologic studies for hepatitis viruses, cytomegalovirus, Epstein-Barr virus, toxoplasma, and HIV. HIV infection is a common cause of immunologic thrombocytopenia. Thrombocytopenia can be the initial symptom of HIV infection or a complication of fully developed clinical AIDS.
Patients with congenital plasma coagulation defects characteristically bleed into muscles, joints, and body cavities hours or days after an injury. Most of the inherited plasma coagulation disorders are due to defects in single coagulation proteins, with the two X-linked disorders, factors VIII and IX deficiency, accounting for the majority. These patients may have severe bleeding and chronic disability and require specialized medical therapy. With rare exceptions, the known disorders prolong either the prothrombin time (PT), partial thromboplastin time (PTT), or both. If they are abnormal, quantitative assays of specific coagulation proteins are then carried out using the PT or PTT tests with plasma from congenitally deficient individuals as substrate. The corrective effect of varying concentrations of patient plasma is measured and expressed as a percentage of a normal pooled plasma standard. The interval range for most coagulation factors is from 50 to 150% of this average value, and the minimal level of most individual factors needed for adequate hemostasis is 25%.
Acquired coagulation disorders are both more frequent and more complex, arising from deficiencies of multiple coagulation proteins and simultaneously affecting both primary and secondary hemostasis. The most common acquired hemorrhagic disorders are (1) disseminated intravascular coagulation (DIC), (2) the hemorrhagic diathesis of liver disease, and (3) vitamin K deficiency and complications of anticoagulant therapy.