Hematology

·         Trousseau syndrome is a chronic form of DIC. When onset of DIC is slow, as is seen in some patients with cancer, compensation can occur. In these patients, a procoagulant state exists, and the patient has a predisposition for arterial and venous thrombosis (unlike in the acute forms of DIC, in which bleeding predominates). The typical laboratory abnormalities associated with acute DIC (thrombocytopenia, elevations in levels of coagulation factors, microangiopathic hemolytic anemia, decreased fibrinogen levels, and elevated D-dimer levels) are usually not present in patients with the chronic form; the exception to this is an elevated D-dimer level. Therapy is directed at the underlying disease. This patient with Trousseau syndrome and DVT should receive subcutaneous heparin if its use is not contraindicated.

·         The deletion of the long arm of chromosome 5 is present in some acute myeloid leukemias and is associated with older age at diagnosis.

The inversion of chromosome 16 is typically present in acute myelomonocytic leukemia (M4 subtype).

The translocation of the long arms of chromosomes 15 and 17 is the mutation associated with acute promyelocytic anemia that results in arrest of cellular differentiation that can be treated with pharmacologic doses of ATRA.

Finally, trisomy 12 is one of several mutations that may result in the development of chronic lymphocytic leukemia.

·         The cryoglobulin associated with hepatitis C typically contains a monoclonal IgMk with rheumatoid factor activity that binds to polyclonal IgG, hence the term ‘mixed cryoglobulin’. The cryoglobulin in CLL usually represents the monoclonal protein produced by the malignant lymphocyte clone. The cryoglobulin in hepatitis B and lupus reflects the immune complexes in the condition and is typically small and polyclonal. Cryoglobulins are not associated with CML.

·         Antithrombin deficiency is an autosomal dominant condition present in 0.02 - 1.1% of the population and is found in 4% of subjects that present with a thromboembolism.

Factor V leiden is a possibility although seems less likely as the inheritance pattern seems more likely to be AD. Similarly as the son had a DVT this would be far less likely with FVLeiden than ATIII as thrmobosis is more often precipitated in females on the OCP.

·         PT (extrinsic)––factors II, V, VII, and X.

·         PTT (intrinsic)––all factors except VII.

·         The peritubular interstitial cells located in the inner cortex and outer medulla of the kidney are the primary sites for erythropoietin production.

·         The proliferation and maturation of platelets take longer than those of either red blood cells (7 to 10 days) or white blood cells (10 to 14 days) and thus are the slowest to recover from an acute bone marrow injury, such as occurs with chemotherapy.

·         In Hemochromatosis, If phlebotomy therapy removes the iron load before diabetes mellitus or cirrhosis develops, the patient’s life expectancy is normal. If cirrhosis develops, however, the risk of hepatocellular carcinoma is increased by more than 200-fold.

·         Serum folic acid levels are less reliable than red blood cell folic acid levels. A serum folic acid level of less than 2 ng/ml is consistent with folic acid deficiency, as is a red blood cell folic acid level of less than 150 ng/ml. Because the combination of folic acid and iron deficiency is common, full expression of megaloblastosis is often blocked, and the patient will have a dimorphic anemia rather than the easily identifiable macro-ovalocytosis.

·         The mutation associated with PNH results in a deficiency of the membrane-anchoring protein phosphatidylinositol glycan class A. Normal human erythrocytes, and probably platelets and neutrophils, modulate complement attack by at least three glycosylphosphatidylinositol (GPI) membrane-bound proteins: DAF (CD55), C8-binding protein (C8BP), and MIRL (CD59). Because the defective synthesis of GPI affects all hematopoietic cells, patients with PNH may have variable degrees of anemia, neutropenia, or thrombocytopenia, or they may have complete bone marrow failure. Recurrent venous occlusions lead to pulmonary embolism and hepatic and mesenteric vein thrombosis, possibly resulting from the release of procoagulant microparticles derived from platelets. Diagnosis is made by specific tests based on fluorescence-activated cell sorter analysis using antibodies that quantitatively assess DAF (CD55) and particularly MIRL (CD59) on the erythrocyte or on the leukocyte surface.

·         Risk factors that predispose to painful crises in Sickle Cell Anemia include a hemoglobin level greater than 8.5 g/dl, pregnancy, cold weather, and a high reticulocyte count.

·         Erythrocytes sensitized to IgG alone are usually removed in the spleen, whereas RBCs sensitized to IgG plus complement or to complement alone are generally destroyed in the liver, because hepatic Kupffer cells carry receptors specific for complement component C3b.

Both an idiopathic variety of autoimmune hemolytic anemia and a variety that occurs secondary to other disorders have been described. Such primary disorders include systemic lupus erythematosus, non-Hodgkin lymphoma (especially chronic lymphocytic leukemia), Hodgkin disease, cancer, myeloma, dermoid cyst, HIV infection, angioimmunoblastic lymphadenopathy with dysproteinemia, hepatitis C infection, and chronic ulcerative colitis.

·         Patients with alpha-thalassemia tend to have lower levels of MCHC and, thus, decreased concentrations of HbS.

·         Some unstable hemoglobins, such as HbE, are susceptible to hemolysis from oxidative stress. This hemoglobinopathy is diagnosed by hemoglobin electrophoresis. However, this disease is seen almost exclusively in individuals from Southeast Asia (Cambodia, Thailand, and Vietnam).

·         Gaisböck syndrome, also known as relative polycythemia, is usually found in men from 45 to 55 years of age; they are most often obese, hypertensive men who may also be heavy smokers.

·         Patients with polycythemia vera who are older than 70 years should be treated with a myelosuppressive agent such as hydroxyurea in combination with phlebotomy.

·         The criteria used to diagnose HES are an unexplained eosinophil count of greater than 1,500/mm3 for longer than 6 months and signs or symptoms of infiltration of eosinophils into tissues. The condition may be caused by excessive IL-5 production by a T cell clone. Manifestations are multisystemic: fever, rash, cough and dyspnea, diarrhea, congestive heart failure, and peripheral neuropathy. The most severe complications involve the heart and CNS. Careful evaluation is necessary to exclude other causes of eosinophilia. Endomyocardial fibrosis (Löffler endocarditis) is a cardiac manifestation of hypereosinophilic syndrome. Eosinophilic deposits may lead to direct injury of the endocardium, followed by platelet thrombi and fibrosis. The cardiac apices can become obliterated, creating a characteristic finding on echocardiography. The mitral and tricuspid valves are affected by the same fibrotic process, resulting in valvular regurgitation.

·         Basophilia (i.e., a basophil count of greater than 150/mm3) is seen in MPDs such as CML, PV, and myeloid metaplasia; after splenectomy; in some hemolytic anemias; and in Hodgkin disease. The basophil count can also be increased in patients with ulcerative colitis or varicella infection.

·         Although less common than leukemoid reactions in adults, leukoerythroblastosis reflects serious marrow stimulation or dysfunction and should prompt bone marrow aspiration and biopsy, unless it occurs in association with severe hemolytic anemia, sepsis in a patient with hyposplenism, or massive trauma.

·         Large granular lymphocyte syndrome is a clonal expansion of CD2+, CD3+, CD8+, CD16+, and CD57+ cells and is frequently associated with rheumatoid arthritis. Patients present with neutropenia, infections, and possibly splenomegaly and may be misdiagnosed as having Felty syndrome. Unlike patients with Felty syndrome, however, these patients present at an older age. Their neutropenia may develop within months of the onset of arthritis and is usually associated with a normal or elevated blood leukocyte (mostly lymphocytes) count.

·         Prevalence of bleeding increases significantly below a threshold of about 10,000 platelets/µl in otherwise asymptomatic patients.

·         Until the cause of the hemolytic transfusion reaction is identified, the patient may only receive type O red cells or AB plasma.

·         Acetaminophen or, if the rigors are particularly severe, meperidine is helpful in the management of febrile transfusion reaction but should be preceded by discontinuance of the infusion.

·         The best results with allogeneic transplantation for AML are obtained in patients undergoing transplantation in first remission, in whom a cure rate of 40% to 70% is reported. As with AML, allogeneic transplantation can cure 15% to 20% of patients with ALL who fail induction therapy or in whom chemotherapy-resistant disease develops; thus, these patients are candidates for the procedure. Allogeneic and syngeneic marrow transplantations are the only forms of therapy known to cure CML. Time from diagnosis influences the outcome of transplantation during the chronic phase. The best results are obtained in patients who receive transplants within 1 year of diagnosis; progressively worse results are seen the longer the procedure is delayed. Use of marrow transplantation in CLL has received only limited attention, probably because of the indolent nature of the disease and its propensity to occur in older patients.

·         Veno-occlusive disease typically occurs in the first few weeks after transplantation. Pathologically, there is cytotoxic injury to the hepatic venulae and sinusoidal endothelium, resulting in vascular blockage (the clinical picture is similar to that of Budd-Chiari syndrome). There is a high mortality, and research continues in the fields of treatment and prevention.

·         The genes that encode HLA class I and II antigens are tightly linked and are typically inherited together. Therefore, there is a one-in-four chance of inheriting the identical haplotype of a sibling.

·         GVHD is quite common in patients receiving allogeneic transplants. The most common manifestation is that of a maculopapular rash, frequently involving the palms and soles. The second most common organ affected is the liver. Symptoms of liver involvement typically include an elevation in levels of transaminase, alkaline phosphatase, and conjugated bilirubin; these changes are the result of damage to the small bile ducts. GI symptoms include diarrhea, anorexia, and crampy abdominal pain. Efforts to prevent GVHD include the use of immunosuppressive agents in the early posttransplantation period. GVHD is most frequently treated with glucocorticoids. It does not cause ARF.

·         Platelets are activated at the site of vascular injury to form a plug to stop bleeding. Platelet activation involves four distinct processes: adhesion, aggregation, secretion, and procoagulant activity. Platelet adhesion is primarily mediated by the binding of GPIb-IX-V complex to von Willebrand protein. Aggregation involves binding of fibrinogen to the platelet fibrinogen receptor GPIIb-IIIa. Congenital deficiency of GPIIb-IIIa or fibrinogen leads to Glanzmann thrombasthenia and afibrinogenemia. The GPIIb-IIIa fibrinogen pathway is the final common course for platelet aggregation. Platelet protein secretion occurs after platelet stimulation, with the release of granules containing serotonin and adenosine diphosphate (ADP), which stimulate and recruit more platelets. Platelet procoagulation involves the assembly of the enzyme complexes in the clotting cascade on the platelet surface. Tissue plasminogen activator is a fibrinolytic factor; its deficiency causes a hypercoagulable state.

·         Antithrombin III, protein C, and protein S are important components of the control mechanisms that modulate coagulation. Protein S circulates in two forms: a free form, in which it is active as an anticoagulant; and a bound, inactive form, in which it is complexed to C4b-binding protein of the complement system. C4b-binding protein acts as an acute phase reactant. The resultant increase in inflammatory state reduces the activity of free protein S, enhancing the likelihood of thrombosis. In this patient, advanced HIV disease is causing an inflammatory state in which the levels of free functional protein S are decreased.

·         Bleeding time should not be used as a general screening test in a preoperative setting. Although once used commonly for screening of platelet disorders, bleeding time has been replaced by the PFA-100. PFA-100 is a newly developed automated test of platelet function. Citrated blood from the patient is aspirated onto a membrane coated with collagen and epinephrine or collagen and ADP in which a central aperture is made. The time it takes for blood flow through the membrane to stop is denoted as the closure time and is a measure of platelet function. The closure time is prolonged in patients with von Willebrand disease or other platelet functional defects. PFA100 should be considered the first-line test for platelet function disorders. Thrombin time is used to test for abnormalities of the conversion of fibrinogen to fibrin. Thrombin time is prolonged in patients with severe liver disease and DIC and those undergoing heparin therapy. Factor VII levels are measured in patients who have a prolonged PT; it is a test of the extrinsic system. Factor XIII is the only clotting factor whose activity is not assessed in PT or PTT; a deficiency should be suspected in an infant who experiences bleeding after circumcision or in an adult with unexplained bleeding.

·         Although most cases of ITP are idiopathic, it is well known that ITP can be associated with a number of underlying conditions, including HIV, viral illnesses (e.g., Epstein-Barr virus [EBV] infection), and autoimmune disease, most notably SLE. In adults, in contrast to children, ITP can present as a smoldering disease. Therapy is recommended for asymptomatic patients whose platelet counts are persistently lower than 20,000 to 30,000/µl and for patients with significant bleeding complications. Although in most patients ITP follows a relatively benign course, serious bleeding complications are occasionally seen. Of these bleeding complications, intracranial bleeding is the most dreaded because it is commonly fatal. Intracranial bleeding is more commonly seen when the platelet count drops below 10,000/µl; other risk factors include advanced age and concomitant medical illness.

·         AT-III deficiency is an autosomal dominant trait that affects nearly 1 in 2,000 people. There are two types of AT-III deficiency: inherited and acquired. The inherited form has two subsets: quantitative deficiency and qualitative deficiency. In some cases, AT-III deficiency may be acquired, as with disseminated intravascular coagulation or severe liver disease or through the administration of I.V. heparin. AT-III normally inactivates factor Xa and thrombin; patients with AT-III deficiency show evidence of continuous factor X activation and thrombin generation. The typical presentation of AT-III deficiency is similar to that of other hypercoagulable states. There is no evidence that AT-III deficiency increases the risk of arterial thrombosis.

·         The two hypercoagulable states more closely related to arterial thrombosis are the antiphospholipid syndrome and hyperhomocystinemia.

·         Because the INR (prothrombin time) is heavily dependent on factor VII, which has a short half-life, it rises fairly quickly after warfarin is begun. However, therapeutic anticoagulation may take several days longer because of the persistence of factor X and prothrombin.

·         DDAVP causes the release of a number of factors and von Willebrand factor from the liver and endothelial cells. This may be useful for patients with mild hemophilia.

·         There are two corrections that need to be made to the reticulocyte count when it is being used to estimate the marrow’s response to anemia. The first correction adjusts the reticulocyte count for the number of circulating red cells (i.e., the percentage of reticulocytes may be increased although the absolute number is unchanged). The absolute reticulocyte count = reticulocyte count * (hematocrit/expected hematocrit). Second, when there is evidence of prematurely released reticulocytes on the blood smear (polychromatophilia), prolonged maturation in the serum may cause a falsely high estimate of daily red blood cell production. Correction is achieved by dividing by a “maturation time correction,” usually 2 if the hematocrit is between 25% and 35%.

·         While the SC route for delivery of vitamin K has long been a primary route of correction for Warferin Overdose, a meta-analysis has shown the SC route to be no better than placebo and inferior to the oral and IV routes, which have similar efficacy.

·         HIT should be suspected in individuals with a fall in platelet count by >50% of pretreatment levels. Usually the fall in platelet counts occurs 5–13 days after starting heparin, but it can occur earlier if there is a prior exposure to heparin, which this patient undoubtedly has because of his mechanical mitral valve replacement. While a platelet count of <100,000/µL is highly suggestive of HIT, in most individuals, the platelet count rarely falls this low. HIT is caused by IgG antibodies directed against antigens on PF4 that are exposed when heparin binds to this protein. The IgG antibody binds simultaneously to the heparin-PF4 complex and the Fc receptor on platelet surface and causes platelet activation, resulting in a hypercoagulable state. Individuals with HIT are at increased risk of both arterial and venous thromboses, although venous thromboses are much more common. Demonstration of antibodies directed against the heparin–platelet factor complex is suggestive of, but not sufficient for, diagnosis because these antibodies may be present in the absence of clinical HIT. The serotonin release assay is the most specific test for determining if HIT is present. Patients should not be switched to low-molecularweight heparin (LMWH). While the incidence of HIT is lower with LMWH, there is cross-reactivity with heparin-PF4 antibodies, and thrombosis can occur. Choice of anticoagulation should be with either a direct thrombin inhibitor or a factor Xa inhibitor. The direct thrombin inhibitors include lepirudin, argatroban, and bivalirudin. Argatroban is the appropriate choice in acute renal failure in association with contrast dye administration for the cardiac catheterization. Argatroban is hepatically metabolized and is safe to give in renal failure, whereas lepirudin is renally metabolized. The factor Xa inhibitors, fondaparinux or danaparoid, are also possible treatments for HIT, but renal metabolism is there. Finally, warfarin is contraindicated as sole treatment for HIT as the fall in vitamin K–dependent anticoagulant factors, especially factor C, can further increase risk of thrombosis and trigger skin necrosis.

·         Embryonic stem cells tend to develop abnormal karyotypes and have the potential to form teratomas. Umbilical cord blood stem cells have less graft-versus-host disease than marrow-derived stem cells and are less likely to be contaminated by the herpes virus. Organ-specific multipotent stem cells are easy to isolate from the marrow but are difficult to isolate from tissues such as the heart and brain. Early studies of bone marrow mesenchymal stem cells have shown that the transplanted cells fuse with cells resident in the organ.

·         Dysfibrinogenemia refers to a constellation of disorders that involve mutations that alter the release of fibrinopeptides, affect the rate of polymerization of fibrin monomers, or alter the sites of fibrin cross-linking. Dysfibrinogenemia is either inherited in an autosomal dominant fashion or acquired. Patients with liver disease, hepatomas, AIDS, and lymphoproliferative disorders may develop an acquired form of dysfibrinogenemia. The presence of altered partial thromboplastin time (PTT) and prothrombin time (PT)/INR reflects an abnormality in coagulation from the prothrombinase complex downstream to fibrin. Correction with a mixing study eliminates factor inhibition as a cause of the coagulation disorder. Other causes of prolongation of the PT and PTT include factor deficiencies in factor V or X, afibrinogenemia or dysfibrinogenemia, and consumption of coagulation factors from DIC.

·         In “mixing study”  the patient’s plasma is mixed with pooled plasma. Correction of the aPTT reflects a deficiency of factors that are replaced by the pooled sample. Failure to correct the aPTT reflects the presence of a factor inhibitor or phospholipid inhibitor. Common causes of a failure to correct include the presence of heparin in the sample, factor inhibitors (factor VIII inhibitor being the most common), and the presence of antiphospholipid antibodies.

·         The differentiation between DIC and severe liver disease is challenging. Both entities may manifest with similar laboratory findings: elevated fibrinogen degradation products, prolonged aPTT and PT, anemia, and thrombocytopenia. When suspecting DIC, these tests should be repeated over a period of 6–8 hours because abnormalities may change dramatically in patients with severe DIC. In contrast, these tests should not fluctuate as much in patients with severe liver disease.

·         The discovery that spectrin deficiency is the sine qua non of hereditary spherocytic red cells led some to hypothesize that primary defects in spectrin would be found in most cases of hereditary spherocytosis. Surprisingly, mutations in a-spectrin (autosomal recessive hereditary spherocytosis) and ß-spectrin (autosomal dominant hereditary spherocytosis) are each present in only about 10% of patients with hereditary spherocytosis. Instead, mutations in ankyrin (autosomal dominant and recessive hereditary spherocytosis; about 40 to 50% of cases) and band 3 (autosomal dominant hereditary spherocytosis; about 20% of cases) are much more common. Mutations in protein 4.2 (autosomal recessive hereditary spherocytosis) are relatively rare except in Japan, where a number of families have been described.

Molecular defects in spectrin, ankyrin, band 3, and protein 4.2 lead to spectrin deficiency as the “final common pathway” that characterizes all red cells with hereditary spherocytosis.