Month: June 2013

Anti-infection Prophylaxis in Cancer Patients With Neutropenia (Risk Evaluating and Patient Selection)

June 26, 2013 Chemotherapy, Hematology, Infectious Diseases, Transplantation No comments , ,

Cancer patients, particularly those with hematologic malignancies, usually have neutropenia, both disease-related and treatment-related, which makes those patients in danger of various types of infection. The way to prevent these patients from infection is prophylactic antibiotics uses. In this post we talk about how to manage neutropenia patients with cancer who are afebrile.

This post is based on the guideline of ASCO.

Assessing the risk of developing an FNE (febrile neutropenic episode)

Evidence data for the evaluation of outpatients is not available, therefore the ASCO Panel considered evidence from studies on inpatients or mixed populations.

Risk for developing an FNE should be systematically assessed (in consultation with infectious disease specialists as needed), including patient-, cancer-, and treatment-related factors.

Risk factors for FNE or for complications resulting form an FNE in oncology patients undergoing systemic chemotherapy are list in Table 1. These risk facors are grouped by characteristics of: patients and their health status, their underlying malignancy, and the chemotherapy regimen they are receiving. Studies cited in Table 1 and others have developed and tested models to predict likelihood of an FNE in the first or a subsequent chemotherapy cycle. On the basis of members’ expert opinion, the Panel recommends that patients starting a new chemotherapy regimen undergo an individualized but systematic assessment of risk for an FNE to evaluate the factors list in Table 1, involving consultation with local infectious disease experts as needed.

Table 1. Factors to Consider in Assessing Risk of and FNE in Patients Unergoing Cytotoxic Chemotherapy for Malignancy.

These risk factors in Table 1 are based on patient, cancer, and treatment modality.

Antibacterial Prophylaxis

Generally, the Panel suggests that clinicaians consider the use of antibacterial prophylaxis only for patients expected to experience profound neutropenia (defined as ANC < 100/μL) likely to last for ≥ 7 days. The Panel does not recommend routine antibacterial prophylaxis for patients with neutropenia that is less severe or of shorter duration. However, prophylaxis might be recommended for patients at high risk of mortality if an FNE occurs.

The literature serach found that antibacterial prophylaxis decreased mortality when compared with pooled controls receiving either placebo or no treatment. However, in these RCTs a majority of patients were undergoing either remission induction (or reinduction) for hematologic malignancy (mostly acute leukemia) or hematopoietic SCT (HSCT). In this population group their rates of febrile episodes, clinically documented infection, microbiologically documented infection, and bacteremia are high. Thus these patients were at high risk for FNE (febrile neutropenic episode).

Few RCTs of antibacterial prophylaxis focused on patients with cancer and neutropenia at low risk for an FNE or infection. In some studies about patients with solid tumors or lymphoma, the prophylaxis significantly decreased documented febrile episodes (core temperature > 38℃) attributed to infection in the first cycle and over the full course of chemotherapy. Also prolhylaxis also significant decreased rates of probable infection and hospitalization for infection, both in the first cycle and over the full course of chemotherapy. However, it did not yield a statistically significant decrease in rates of severe infection (infection-related sepsis syndrome, death, or both) or infection-related mortality.

A subset analysis in one meta-analysis pooled data from the RCT for patients with solid tumor or lymphoma reported a statistically significant decrease in all-cause mortality during the first month of chemotherapy. However, the absolute difference in 30-day mortality was modest and the prophylaxis did not significantly decrease all-cause mortality by the end of follow-up. These data suggest that it is not recommended to routinely use prophylactic antibacterial therapy in low-risk patients.

Thus, we recommend that clinicians limit use of antibacterial prophylaxis to patients at high risk for an FNE associated with prolonged severe neutropenia (ANC < 500/µL). The risk for FNE or infection are importantly determined by the expected duration and depth of neutropenia, and other factors in Table 1. However, because direct evidence is lacking, it is difficult to define risk thresholds for the two important variables above. Thus, ASCO Panel recommend that unless one or more other high-risk features of Table 1 are present, antibacterial prophylaxis should be limited to patients expected to have profound neutropenia (ANC < 100/µL) for at least 7 days.

Antifungal Prophylaxis

For the fungal infection, three meta-analyses reported that when compared with controls, systemic antifungal prophylaxis significantly decreased mortality attributed to fungal infections. Also the need for subsequent full-dose parenteral antifungal therapy was decreased and the incidence of systemic, invasive, and/or superficial fungal infections decreased too. Again, however, most patients randomly assigned in these RCTs were at high risk for IFI (invasive fungal infection) resulting from HSCT, induction chemotherapy for acute leukemia, or other treatments that caused lengthy durations of profound neutropenia.

The most recent review pooled data from 33 RCTs found a statistically significant decrease in fungal infection-related mortality and all-cause mortality at the end of follow-up. However, metaregression analysis showed statistically significant associations between the proportion of randomly assigned patients being treated for leukemia with the treatment effects of systemic antifungal prophylaxis in both overall mortality and risk for IFI.

Data from the most recent meta-analysis of RCTs of antifungal prophylaxis also showed that pooled IFI rates (either candidiasis or aspergillosis) among controls were approximately 6% across 24 studies of patients undergoing treatment for acute leukemia and > 10% across four studies of patients undergoing HSCT, each associated with lengthy duration of profound neutropenia. Thus, the ASCO Panel recommends limiting antifungal prophylaxis to patients at substantial risk for IFI (> 6% to 10%), which is profound neutropenia (ANC < 100//µL) for at least 7 days.

                                                                                                                                               Table 2. Risk Factors for Invasive Mold Infection

Risk Factors for IFI
  • Prolonged profound peutropenia (ANC < 100/µL for > 7 days) in the context of intensive remission-induction or reinduction therapy for acute leukemia in environments where the risk for invasive aspergillosis exceeds 6%
  • Prolonged (> 21 days) severe neutropenia (ANC < 500/µL), lymphocytopenia (ALC < 500/µL), or monocytopenia (AMC < 150/µL) among allogeneic HSCT recipients experiencing graft failure
  • Use of purine analogs (eg, fludarabine) to treat malignancy for pre-HSCT conditioning
  • Use of intensive immunosuppression for treating GVHD
  • Reactivation of cytomegalovirus
  • Iron overload states
  • A previous documented invasive mold infection
  • Environmental exposures associated with personal habits, outside activities, or indoor activities
Of note: many of these risk factors may interact to enhance the risk for mold infection.

Prophylaxis for Pneumocystis jirovecii Infection

Patients receiving chemotherapy regimens associated with a risk > 3.5% for pneumonia resulting from Pneumocystis jirovecii (PCP; eg, those with ≥ 20 mg of prednisone equivalents daily for ≥ 1 month or those based on purine analogs) are eligible for prophylaxis.

Retrospective analyses suggest those at greatest risk are patients undergoing intensive induction (or salvage reinduction) for acute leukemia, allogeneic bone marrow transplantation (particularly if receiving alemtuzumab), or treatment with either high-dose corticosteroids (eg, ≥ 20 mg of prednisone equivalents daily for ≥ 1 month) or purine analogs that deplete T cells such as fludarabine or cladribine. Additionally, a recent report suggests the regimen combining rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone every 2 weeks (R-CHOP-14) is associated with elevated risk for PCP (10% to 15%), although the regimen with the same drugs every 3 week (classical R-CHOP) is not. Another recent retrospective analysis suggests that CD4+ lymphocyte counts ≤ 200/µL predicted a higher risk (approximately 19%) for PCP in patients treated for B-cell non-Hodgkin lymphoma.

Prophylaxis for Reactivation of Hepatitis B Virus (HBV) Infection

Antiviral prophylaxis should be offered to patients know to be at substantial risk for reactivation of hepatitis B virus (HBV) infection.

Reactivation of HBV infection after treatment for malignancy has been reviewed extensively. Guidelines from several other organizations suggest that patients at risk for HBV reactivaton should be screened for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B core antigen (anti-HBc). Howver, ASCO Panel concluded that available evidence was insufficient to determine the net benefits and harms of routine screening for chronic HBV infection in all individuals with cancer about to receive (or already receiving) cytotoxic or immunosuppressive therapy. The Panel recommended a more targeted approach to HBV testing, using clinical judgment to select patients at risk who are about to receive or already receiving highly immunosuppressive treatments including, but not limited to, HSCT and regimens that include rituximab.

Three groups with a history of prior exposure to HBV are at risk: patients with chronic infection and viremia, chronic inactive carriers (positive for HBsAg for ≥ 6 months but with serum HBV DNA < 2,000 IU/mL and normal serum levels of hepatic transaminases), and those with immunity against HBV because of past exposure. Factors that may increase reactivation risk include male sex, younger age, hepatic transaminase levels > the normal range or HBV DNA > 3 × 105 copies/mL before cytotoxic therapy begins, dose-intense chemotherapy, and severe immunosuppression.

Prophylaxis for HSV and VZV

Evidence summarized in some revies suggests that most HSV (herpes simplex virus) or VZV (Varicella-Zoster virus) infections in patients undergoing treatment for malignancy are the result of reactivation of latent virus from prior exposure; new primary infections are uncommon.

In the absence of HSV prophylaxis, reactivation has been reported in 37% to 57% of patients undergoing intensive chemotherapy for hematologic malignancies and in 68% to 90% of those undergoing myeloablative allogeneic HSCT.

Reactivation of latent VZV, present in most adults, results in herpes zoster; complications may include postherpetic neuralgia, zoster ophthalmicus, scarring, or bacterial superinfection. Among patients with hematologic malignancies, VZV reactivaton is reportedly uncommon after imatinib for chronic myeloid leukemia (2.6%) but more frequent after fludarabine or alemtuzumab for chronic lymphocytic leukemia (10% to 15%), treatment for Hodgkin lymphoma or autologous HSCT (25%), and bortezomib for multiple myeloma (11% to 15%). VZV reactivation occurs in 30% to 60% of those who undergo allogeneic HSCT but is typically delayed until after engraftment. The median time to reactivation among such patients has been reported to be approximately 8 months, and approximately one in five may develop postherpetic neuralgia.

It is recommended that HSV or/and VZV seropositive patients undergoing therapy for certain hematologic mailignancies should be given prophylais to prevent reactivation of infection because of HSV.

Prophylaxis for Influenza

Seasonal influenza immunization is recommended for all patients undergoing treatment for malignancy and for all family and household contacts.

The Management of Myelodysplastic Syndromes (MDS)

June 21, 2013 Chemotherapy, Cytogenetics, Hematology, Pharmacotherapy, Therapeutics, Transplantation 3 comments , , , ,

The myelodysplastic syndromes (MDS) are a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias. MDS are diagnosed in slightly more than 10,000 people in the United States yearly, for an annual age-adjusted incidence rate of approximately 4.4 to 4.6 cases per 100,000 people. They are more common in men and whites. The syndromes may arise de novo or secondarily after treatment with chemotherapy and/or radiation therapy for other cancers or, rarely, after environmental exposures. De novo MDS is called primary MDS while the other is called secondary MDS. Indeed, the natural history of secondary MDS is expected to be worse than primary MDS. In this post we mainly focus on primary MDS and any recommendations for therapies here should be interpreted with caution when considering patients with secondary MDS.

Risk and Prognosis

There are three scoring system to evaluate the risk and prognosis of myelodysplastic syndromes (MDS) including: IPSS (International Prognostic Scoring System, 1997), WPSS (the WHO classification-based Prognostic Scoring System), and IPSS-R (Revised-IPSS, 2012).

IPSS (table 1) is the most widely used classification system for patients with MDS. 3 factors including the percentage of bone marrow myeloblasts, the diagnostic cytogenetics, and the number of cytopenias are used to generate a prognostic score. However, there are some limitations of IPSS: 1. the lack of inclusion of secondary (after prior cytotoxic therapy) MDS cases, 2. the inclusion of many patients now considered to have AML, 3. the lack of “treated” cases, and 4. the unknown impact of currently available therapies.

Table 1. The International Prognostic Scoring System (IPSS) for MDS.

Prognostic variable00.
Bone marrow blasts (%)< 55-1011-2021-30
Cytopenias, n0 or 12 or 3


ScoreIPSS subgroupMedian survival (years)
> 2.5High0.4

*Good: normal, -Y, del(5q), del(20q); intermediate: other abnormalities; poor: complex (≥ 3 abnormalities) or chromosome 7 anomalies.
†Platelets < 100,000/μL; hemoglobin < 10 g/dL; neutrophils < 1,800/μL.

Reproduced from Greenberg P, et al. Blood. 1997;89:2079-88 © 1997 by The American Society of Hematology.

WPSS (table 2) makes use of the WHO subclassifications and supports the intuitive notion that the need for red cell transfusions predicts for a worse prognosis. The risk groups of WPSS are very low (0 point), low (1 point), intermediate (2 points), high (3 to 4 points), or very high (5 to 6 points). The median survival and risk of progression to AML at 5 years is 140 months/3%, 66months/14%, 48 months/33%, 26 months/54%, and 9 months/84%, respectively. Note that two categories of RAEB were recognised by the WHO classification, in which RAEB-1 and RAEB-2 with 5-9% and 10-19% blasts, respectively.

Table 2. WHO classification-based Prognostic Scoring System.

WHO classification-based Prognostic Scoring System for MDS.

In IPSS-R (table 3) bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation.

Table 3. Revised-IPSS

Compared with IPSS, the IPSS-R model showed effective separation of the IPSS patient risk categories and more effectively discriminated prognostic risk for these patients than the IPSS. Data indicated that 99% of the patients in the IPSS-R Very low and Low risk subgroups encompassed those who had been classified as IPSS Low and Intermediate-1; 81% of those in the IPSS-R High and Very high risk subgroups had been classified as IPSS Intermediate-2 and High.

The Management of MDS

After the evaluation of risk and prognosis, comes the management of MDS. Which patient should be treated and how?

Figure 1. Approach to Therapy of MDS Patients

Myelodysplasia is an incurable disease with non-transplantation therapy, but highly variable in its natural history. Treatment considerations must take into account many factors, including the pathologic diagnosis, the prognosis based on the IPSS, WPSS, or IPSS-R, the unique disease features in that particular patient, feasibility of performing a clinical trial, the appropriateness of a bone marrow transplantation, and indeed the philosophy of the patient and the family concerning his or her care.

In addition, if the patient has secondary MDS, tolerability of therapy is probably worse because of previous exposure to DNA-damaging agents and predicting how patients with secondary MDS will respond is difficult because of a lack of data and exclusion of such patients from most clinical trials.

Until now MDS remains a challenge for clinicians because of the older patient milieu, the disease heterogeneity, and the lack of effective medical therapy. And the choice between therapies is hampered by a relative lack of prospecitve randomized trials.

Firstly, what we should do after evaluation is to determine whether to treat or not. There are patients who have MDS based on sound pathologic and clinical criteria who might best be served by observation. Treatment should be reserved, and potentially the diagnosis transmitted to the patient and family, only if there are symptoms resulting from anemia or other cytopenias or perhaps presymptomatic anemia or severe thrombocytopenia.

Once the decision to treat is made, different approaches are available. However, we don’t know the standard algorithm beacuse lack of prospective randomized trials. We lack of effecive therapeuitc approach for this disease at present.

Supportive Care

Supportive care includes blood components transfusion, treatment of neutropenia and possible infections, and bone marrow stimulation.

Patients with moderate-to-severe anemia require RBC replacement. Transfusing packed RBCs for severe or symptomatic anemia benefits the patient temporarily, only for the life span of the transfused RBCs (2-4 wk). Patients with congestive heart failure may not tolerate the same degree of anemia as young patients with normal cardiac function, and slow or small-volume (eg, packed RBCs) transfusions with judicious use of diuretics should be considered.

Patients with multiple RBC transfusions might develop transfusion-induced iron overload which can incur significant damage of the liver, heart, pancreas, and other tissues. Current guidelines recommend starting iron chelation therapy in those patients who have received 20-25 units of packed RBCs or who have a serum ferritin level of >1000 μg/L. However, there are absolutely no definitive data concerning the frequency of such complications, let alone whether patient outcomes might be improved by the use of chronic iron chelation therapy. Tow iron chelation agents have been approved by FDA for the indication of iron overload: deferoxamine and deferasirox.

The notion of using hematopoietic growth factors to treat the cytopenias of patients with MDS is attractive but certainly limited by the problem of an intrinsically deranged and therefore potentially unresponsive marrow stem cell. Nonetheless, virtually every patient with MDS and anemia at some point receive an erythropoietic growth factor. However, there is incomplete information and confusion about the likelihood of response, the optimal dose, and whether to use a short- or long-acting agent. 25% of patients with anemia will respond (reduce their transfusion requirement by at least 50% or increase hemoglobin by 1g/dL) and response can take 8 weeks or more. It is common practice to increase the dose of erythropoietic growth factor once or even twice before concluding that the patient is unresponsive to single-agent erythropoietin. Patients who are not ransfusion dependent at baseline or who have relatively low intrinsic levels of serum erythropoietin (< 500 mIU/mL) are more likely to respond with response duration in 1 to 2 years. Lack of response could be the result of insufficient iron stores, but the presumptive usual problem is an intrinsically unresponsive marrow. The hemoglobin response to erythropoietin may be improved from 25% to 40% with the addition of low-dose granulocyte colony-stimulating factor.

Platelet transfusion is beneficial to stop active bleeding in thrombocytopenic patients, but the life span for transfused platelets is only 3-7 days. Routine use of platelet transfusions to support nonbleeding (even severly) thrombocytopenic patients is not advisable. The ASCO clinical guideline for prophylactic platelet transfusion also suggests that many of these patients can be observed without prophylactic transfusion, reserving platelet transfusion for episodes of hemmorrhage or during times of active treatment.

There are no useful currently available cytokines for thrombocytopenic MDS patients.

Neutropenia without a history of infection is a poor justification for initiation of therapy. Randomized studies did not demonstrate any real clinical benefit of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. If neutropenia with infection, manage patients with board-spectrum antibotics necessary. If with systematic serious fungal infection antifungal agents should be given.


The HSCT is the only modality to cure this disease. But it dose not mean every patient diagnosed with MDS should be referred for such a procedure. Patients can reasonably safely be transplanted in the standard (myeloablative) conditioning regimen up to age 55 to 60 years. The outcome after transplantation for those with indolent disease is superior to that in patients with more aggressive MDS. Recent data suggest that lower risk paitents (according to the WHO or WPSS) do very well with allogeneic transplanation, whereas those with 5% to 20% marrow blasts have only a 25% to 28% 5-year overall survival.

Because of the possibility of diminishing overall life expectancy resulting from treatment-related mortality in those with good prognosis, it is recommended that allogeneic transplantation be used in low and intermediate-1 IPSS patients only after disease progression, whereas patients with more aggressive histology/prognosis should be transplanted immediately on recognition that a donor exists.

Treatment-related mortality difference between matched-sibling transplantation and matched unrelated donor transplantation is very small, as a result there is no distinction about whether there is a family donor or a unrelated donor.

For patients between 55 and 70 to 75 years of age, it is reasonable to consider a reduced-intensity conditioning (RIC) regimen. It is clear that treatment-related mortality associated with RIC is no higher than that seen with full transplantations in younger patients. However, the major problem of this approach is that we lack of long-term data with regard to disease relapse.

Another problem for transplantation, particularly for RIC, is the excess marrow myeloblasts or the relevance of disease control. It is clear that in AML patients fewer marrow blasts at the time of transplantation portend for a better outcome than if the transplantation is done in the presence of more fulminant disease. But in MDS patients the indication of chemoresponsivity or the value of pretransplantation cytoreduction is unclear. Nonetheless, the presence of more than 5% to 10% blasts in the marrow of an MDS patient probably makes transplantation, particularly with RIC, less likely to succeed. So it is therefore reasonable to administer one or 2 cycles of “MDS-induction therapy” with a DNA-hypomethylating agent in an attempt to “perform an in vivo purge” of the marrow blasts before the allogeneic procedure.


For MDS patients with “5q-” syndrome, or with 5q- cytogenetic abnormality alone without the syndrome, or 5q- with other cytogenetic abnormalities, an effective therapy has emerged. Lenalidomide produces a 67% rate of transfusion independence and major increases in the hemoglobin. Although the FDA-approved label for lenalidomide calls for dose modification if myelosuppression is noted, recent data suggest that a more aggressive dosing scheme might be considered if optimal support can be provided. The median time to response is 4.4 weeks; the median duration of the response has not yet been reached. However, the clinical trial detailing this impressive responsive rate was restricted to those with low-risk and IPSS-1 disease, platelet counts greater than 50,000, and neutrophil counts greater than 500.

But with the rationale of lenalidomide implying that major disease-modifying activity is possible because of likelihood of elimination of the karyotypically abnormal clone, lenalidomide dose appear to be a major advance for patients with 5q- chromosome abnormalities and should be used as initial therapy in such patients who require treatment.

Immunosuppressive Therapy

The patient subgroup who might benefit from immunosuppressive is difficult to define. The rationale of immunosuppressive therapy is that immune-mediated suppression of normal stem cell function, analogous to the situation in aplastic anemia, has been postulated to account for cytopenias in some MDS patients. Selected patients treated with either cyclosporine A or an antihympcyte-globulin (ATG) based regimen can experience improvements in cytopenia in about one-third to one-half of the cases. Patients who are HLA D15 positive, who tend to be younger, or who have lower platelet count irrespective of marrow cellularity are more likely to respond to such immunosuppressive manipulations. Conversely, another study suggests that hypocellularity and low IPSS score are predictors of response to immunosuppressive therapy. Of note, studies to define the optimal patients in whom such therapy is appropriate remain to be developed.

Table 4. Proposed Modified International WorkingGroup (IWG) Response Criteria for MDS

Table 5. Proposed Modified International WorkingGroup (IWG) Response Criteria for Hematologic Improvement

Cheson et al. Blood. 2006;108:419‐425.

Cheson et al. Blood. 2000;96:3671‐3674. (The old IWG response criteria)

Patients who are non 5q- and ineligible for immunosuppressive therapy and transplantation

Lenalidomide. A trial including 214 patients with non 5q- MDS were treated with lenalidomide at a starting dose of 10 mg daily (either continuously or on a cycle of 21 days on, 7 days off) were recently published. A total of 26% of these patients experienced a reduction in their transfusional needs, which is roughly comparable with what is often obtained with erythropoietin or DNA-hypomethylating agents. The median time to response was 4 weeks and the duration of response was 7 months.

However, the eligibility for this trial required low or intermediate-1 IPSS risk MDS and excluded patients with secondary MDS or those who platelet counts were less than 50,000/μL or whose neutrophil counts were less than 1000/μL.

DNA-hypomethylating agent. Clinically, those with MDS subtypes with excessive numbers of marrow myeloblasts resemble the situation in high-risk (older patient or adverse chromosome prognosis) AML. The class of drugs most useful in MDS and applicable to all subtypes are the DNA-hypomethylating agents 5-azacitidine and decitabine.

Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

Ont clinical trial showed that an early crossover design dampened any potential survival benefit attributable to azacitidine. However, the results demonstrated a delay in time to transformation to AML in those initially randomized to the study drug. There was a much higher response rate in the experimental  arm, and an ancillary quality of life study proved that patients randomized to azacitidine fared better.

We administer 4 cycles at 75 mg/m2 subcutaneously for 7 days every 28 days, rarely make dose adjustments, and do a bone marrow after cycle 4 to determine whether additional cycles are indicated. However, for many, the decision to continue or not is relatively difficult.

Platelet Transfusion for Patients With Cancer (Part Three)

June 16, 2013 Hematology, Therapeutics No comments , , ,

If the patient is transfused with platelet alloimmunization might happen, including alloimmunization due to RhD antigens or non-histocompatibility. And the patient might develop refractoriness to platelet transfusion.

RhD Antigen-Induced Alloimmunization

Platelets do not express Rh antigens on their surface, but quantity or RBCs in platelet preparations is sufficient to induce Rh sensitization, even in immunosuppressed cancer patients. Different studies have documented that anti-D antibodies can be detected in 7.8% to 19% of heterogeneous groups of RhD-negative cancer patients exposed to RhD antigens via transfusion.

Two small studies have demonstrated that RhD immunoprophylaxis can prevent the development of anti-D in this setting. Thus, if platelets from an Rh-positive donor or platelets from a donor of unknown Rh phenotype are given to an Rh-negative recipient, administration of Rh immunoproplylaxis should be considered, especially for younger female patients who might become pregnant after successful treatment. Because of the thrombocytopenia, it is preferable to use a preparation of anti-D that can be administered intravenously (IV).

The amount of anti-D immunoglobulin necessary to prevent sensitization depends on the number of contaminating RBCs in the PCs. Generally, a dose of 25 μg (125 IU) of anti-D immunoglobulin will protect against 1 mL of RBCs. If possible, the immunoglobulin should be given before or immediately after the transfusion, although, as in the obstetrical setting, it may still be efficacious if given within 72 hours of exposure to the RhD-positive RBCs.

Alloimmunization Against Histocompatibility Agtigens

Besides RhD antigen alloimmunizaton due to non-histocompatibility is a problem when the patients with cancer needs multiple platelet transfusions. Alloimmunization against histocompatibility antigens ocurs in many recipients of multiple random donor platelet transfusions and is the most important long-term complication of platelet transfusion. Recent experience suggests that between 25% and 35% of newly diagnosed patients with AML will produce lymphocytotoxic antibody and become alloimmunized and refractory to nonhistocompatible platelet transfusions. However, as many as 40% to 60% of apparently histocompatible platelet transfusion administered to alloimmunized patients are unsuccessful and when histocompatible donors are not available, the management of alloimmunized patients is difficult.

As a result, the elimination of alloimmunization would greatly simplify platelet transfusion therapy. Vitro and animal studies suggest that the leukocytes contaminating platelet preparations are the primary stimulus for alloimmunization. It seems that presentation of class I and class II antigens by intact leukocytes is required for initial processing by the immune system. Because platelets do not express class II histocompatibility antigens, it is likely that it is the leukocyte that serves as the costimulus.

To reduce the incidence of alloimmunization by leukocytes, different methods exist secondary to filtration of leukocytes or modification of the antigen presenting capacity of leukocytes. Filtration of platelets before transfusion can make 3 to 4 log reduction in leukocyte contamination platelets that obtained either by apheresis or PCs. It has been shown that ultraviolet B (UVB) irradiation can abolish reactivity in mixed lymphocyte reactions and that doses of UVB irradiation can be identified that do not affect platelet function in vitro. However, two recently published small trials failed to show benefit from leukocyte filtration, and as a result of the filtration up to 25% ~ 35% of platelets will be lost.

To help address these concerns, a large, randomized multi-institutional trial (the TRAP trial) was recently completed. In the trial 603 patients with newly diagnosed AML receiving initial induction therapy were randomized to receive the following approaches: pooled PC (control group); filtered PC (leukoreduced); single donor, filtered platelets collected by apheresis; or pooled PC that had been UVB irradiated. All manipulations were performed at blood bank, not at the patient bedside. All RBC transfusions were also leukodepleted by filtration. The target level  of leukocytes is less than 5 × 106 per transfusion. Compared with the control group (45%), there was a statistically significant reduction (17% to 21%) in the formation of lymphocytotoxic antibody (anti-HLA antibody) in all three groups receiving modified platelets.

Thus, the conclusions is that it is appropriate to provide leukoreduced RBC and platelet products to newly diagnosed patients with AML and probably other types of acute leukemia. Although randomized trials have not been conducted in other patients groups, it is likely that alloimmunization can also be decreased in patients with other cancers receiving chemotherapy. For patients not receiving chemotherapy and need multiple platelet transfusions, there  are not data yet. But we would favor this approach in these patients as well.

Of note, this approach should be used only for patients expected to require multiple platelet transfusions during their treatment courses and is not indicated for patients with cancer receiving RBCs or therapies that do not produce significant and sustained thrombocytopenia. It should also be noted that only a subfraction of patients benefit from any successful approach to reduce the rate of alloimmunization. Why? Because only 30% to 40% of patients become alloimmunized without leukocyte-reduced procedure and not all of these 30% to 40% of patients achieve CR and receive intensive postremission therapy. This is of importance because there was only a modest reduction in the incidence of refractoriness to transfusion in the TRAP trial. And aslo since the antibodies often developed after 3 to 4 weeks in the TRAP trial, at a time when the patients may no longer required platelet transfusion. So these reasons make that only a subfraction of patients benefit from the prevention of alloimmunization.

Diagnosis, Evaluation and Treatment of Refractoriness to Platelet Transfusion

If the patient have a poor increment after two ABO-compatible platelet transfusions which stored less than 72 hours, it is suggested that the most likely reason is alloimmunization. To confirm, lymphocytotoxicity assays or platelet antibody testing may be useful since approximately 90% of patients with platelet transfusion alloimmunization will have alloantibody. Of note that other reasons including drug-related antibodies, hypersplenism, severe DIC, shock, and massive hemorrhage may also result in poor platelet increments.

The method to evaluate the platelet recovery due to transfusion is called “CCI” formula which based on estimated blood volume or body-surface size of the patient as well as the number of platelets in the infused product. The TRAP trial use the following formula to evaluate: CCI = absolute increment (μL)× body-surface area (m2)/number of platelets transfused × 1011. For instance, if transfusion of 4 × 1011 platelets produced an increment of 40,000/μL (40 × 109/L) in a 2-m2 recipient, the CCI = 40,000 (μL) × 2 (m2)/4 = 20,000. If the CCI ≥ 5,000 means a satisfactory response to the platelet transfusion(s). While the platelet increment is determined by subtracting the pretransfusion platelet count from the count determined 1 hour after transfusion, however, identical results are obtained by using a 10-minute posttransfusion count, which is simple to obtain because the patient must be seen when the transfusion is completed to switch the IV bags. Although it would be desirable to obtain immediate posttransfusion increments after all platelet transfusions, it is reasonable to obtain such increments in nonbleeding hospitalized patients if the day-to-day increments are not satisfactory and after all transfusions to outpatients.

Patients with alloimmune refractory thrombocytopenia, as defined above, are best managed with platelet transfusions from donors who are HLA-A and HLA-B antigen selected. For patients whose HLA type cannot be determined, who have uncommon HLA types for which suitable donors cannot be identified, or who do not respond to HLA matched platelets, histocompatible platelet donors can often be identified using platelet cross-matching techniques (besides HLA matching technique, there is another way called cross-matching to identify the histocompatibility. These two techniques are complementary). Note that there is no evidence that alloimmunized patients benefit from nonmatched prophylactic platelet transfusions that do not produce posttransfusion increments, and we recommend such patients be transfused only for hemorrhagic events.

The Management of Disseminated Intravascular Coagulation (DIC)

June 10, 2013 Anticoagulant Therapy, Hematology, Pharmacotherapy, Physiology and Pathophysiology, Therapeutics No comments

Disseminated intravascular coagulation (DIC) is characterized by systemic activation of blood coagulation, which results in generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing to multiple organ dysfunction syndrome (MODS). Consumption and subsequent exhaustion of coagulation proteins and platelets may induce severe bleeding.

The International Society on Thrombosis and Haemostasis has suggested the following definition for DIC: An acquired syndrome characterized by the intravascular activation of coagulation with a simultaneously occurring thrombotic and bleeding problem, which obviously complicates the proper treatment.

DIC is not itself a specific illness; rather, it is a complication or an effect of the progression of other illnesses. It is always secondary to an underlying disorder and is associated with a number of clinical conditions such as sepsis and severe infection, trauma, organ destruction, malignancy, and so on.

DIC can be divided into acute DIC and chronic DIC. Acute DIC develops when sudden exposure of blood to procoagulants generates intravascular coagulation. Compensatory hemostatic mechanisms are quickly overwhelmed, and as a result, a severe consumptive coagulopathy leading to hemorrhage develops. In contrast, chronic DIC reflects a compensated state that develops when blood is continuously or intermittently exposed to small amounts of procoagulants. Compensatory hemostatic mechanisms are not overwhelmed, and there may be little obvious clinical or laboratory indication of the presence of DIC.


Four simultaneous mechanisms seem to result in the hematologic derangements seen in DIC. They are TF (tissue factor)-mediated thrombin generation, dysfunctional physiologic anticoagulant mechanisms, impaired fibrin removal due to depression of the fibrinolytic system, and inflammatory activation.

Thrombin generation and tissue factor

Exposure to TF in the circulation occurs via endothelial disruption, tissue damage, or inflammatory or tumor cell expression of procoagulant molecules (including TF). TF activates coagulation by forming TF-VIIa complex which activates thrombin (the complex cleaves fibrinogen to fibrin while simultaneously causing platelet aggregaton), which is the extrinsic pathway of coagulant cascades. After produced by TF/factor VIIa pathway, thrombin amplifies both clotting and inflammation.

While the extrinsic pathway plays an important role in thrombin generation in DIC, the intrinsic pathway may also be activated in DIC, but it appears not to play an important role. The actual source of the TF has not been established with certainty. TF may be expressed on mononuclear cells in vitro, on polymorphonuclear leukocytes, on circulating monocytes of patients with severe infection, and on injured endothelial cells. Whereas, the  importance of the role TF expresson on injured endothelial play remains to be determined.

Impaired coagulation inhibitor systems

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Impaired functioning of various natural regulating pathways of coagulation activation may amplify further thrombin generation and contribute to fibrin formation.

Three main substances consist the coagulation inhibitor systems including antithrombin, protein C, and TF pathway inhibitor (TFPI).

Usually patients with DIC have markedly reduced antithrombin level. The causation may be that antithrombin is continuously consumed by ongoing activation of coagulation, elastase produced by activated neutrophils degrades antithrombin, further antithrombin is lost to capillary leakage during DIC, and that production of antithrombin is impaired secondary to liver damage resulting from underperfusion and microvascular coagulation.

Protein C along with protein S, severs as a major anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin when complexed on the endothelial cell surface with thrombomodulin. Activated protein C combats coagulation by proteolytic cleavage of factors Va and VIIIa and proteolyzes RAR1 when bound to the endothelial cell protein C receptor (EPCR). Impaired functioning of the protein C pathway is mainly due to down-regulation of thrombomodulin expression or its inactivation by cellular reactive oxygen species on endothelial cells by proinflammatory cytokines. Also the level of protein C is reduced during DIC as a result of continuously consumption, lost to capillary leakage and so on (similar to those described for antithrombin). So both low level and diminished activation of protein C result in the impaired anticoagulation function of coagulation inhibitor systems.

TF pathway inhibitor (TFPI) is another anticoagulant rechanism that is disabled in DIC. TFPI reversibly inhibits factor Xa and thrombin (indirectly) and has the ability to inhibit the TF-VIIa complex. During the DIC TFPI is relative insufficient which reduces the function of the coagulation inhibitor systems.

Defective fibrinolysis

The intravascular fibrin produced by thrombin is normally eliminated by a process termed fibrinolysis. Experimental models indicate that at the time of maximal activation of coagulation, the fibrinolytic system is largely shut off. Experimental bacteremia and endotoxemia result in a rapid increase in fibrinolytic activity, most probably caused by release of plasminogen activators from endothelial cells. However, this profibrinolytic response is almost immediately followed by suppression of fibrinolytic activity due to a sustained increase in plasma levels of PAI-1.

However, rare cases of DIC are characterized by a severe hyperfibrinolytic state on top of an activated coagulation system. Examples of such situations are the DIC that occurs as a complication of acute promyelocytic leukemia (APL/AML-M3) and some forms of adenocarcinoma. Clinically, these patients suffer from severe bleeding.

Inflammatory activation

Inflammatory and coagulation pathways interact in substantial ways. It is clear that there is cross-communication between the 2 systems, whereby inflammation gives rise to activation of the clotting cascade and the resultant coagulation stimulates more vigorous inflammatory activity. For example, thrombin produced by TF/factor VII pathway can amplify inflammation.

Screen Shot 2014-10-26 at 10.30.24 PMEtiology

Several disease states may lead to the development of DIC, generally via 1 of the following 2 pathways: 1. A systemic inflammatory response, leading to activation of the cytokine network and subsequent activation of coagulation (e.g., in sepsis or major trauma);2. Release or exposure of procoagulant material into the bloodstream (e.g., in cancer, crush brain injury, or in obstetric cases). These disease states include infections, maligancies, obstetric cases, transfusion related cases such as hemolytic reactions, trauma, and others.

Bacterial infection (in particular, bloodstream infection) is commonly associated with DIC. There is no difference in the incidence of DIC between patients with gram-negative and those with gram-positive sepsis. Systemic infections with other microorganisms, such as viruses and parasites, may lead to DIC as well. Factors involved in the development of DIC in patients with infections may be specific cell membrane components of the microorganism or bacterial exotoxins. These component cause a generalized inflammatory response, characterized by the systemic occurrence of proinflammatory of cytokines.

Table 1. Causes of Acute (Hemorrhagic) Disseminated Intravascular Coagulation

InfectiousBacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial) Viral (eg, HIV, cytomegalovirus [CMV], varicella-zoster virus [VZV], and hepatitis virus) Fungal (eg, Histoplasma)Parasitic (eg, malaria)
MalignancyHematologic (eg, acute myelocytic leukemia) Metastatic (eg, mucin-secreting adenocarcinoma)
ObstetricPlacental abruptionAmniotic fluid embolism Acute fatty liver of pregnancyEclampsia
TraumaBurns Motor vehicle accidents Snake envenomation
TransfusionHemolytic reactions Transfusion
OtherLiver disease/acute hepatic failure* Prosthetic devices Shunts (Denver or LeVeen)Ventricular assist devices
*Some do not classify this as DIC; rather, it is liver disease with reduced blood coagulation factor synthesis and reduced clearance of activate products of coagulation.


DIC may occur in 30-50% of patients with sepsis, and it develops in an estimated 1% of all hospitalized patients. The prognosis of DIC depends on the severity of the coagulopathy and on the underlying condition that led to DIC. However, assigning numerical figures to DIC-specific morbidity and mortality is difficult. In general, if the underlying condition is self-limited or can be appropriately handled, DIC will disappear, and the coagulation status will normalize. A patient with acute hemorrhagic DIC that is associated with metastatic gastric carcinoma likely has a lethal condition that does not alter patient demise, regardless of treatment. On the other hand, a patient with acute DIC associated with abruptio placentae needs quick recognition and obstetric treatment; the DIC will resolve with the treatment of the obstetric catastrophe.


Diagnosis of DIC can be difficult, especially in cases of chronic. Here we focus on acute DIC because it much worsen than chronic DIC with higher morbidity and mortality. The diagnosis of DIC relies on multiple clinical and laboratory determinations. The International Society on Thrombosis and Haemostasis (ISTH) developed a scoring system for the diagnosis of overt DIC that makes use of laboratory tests available in almost all hospital laboratories. The presence of an underlying disorder known to be associated with DIC (see Etiology) is a sine qua non for the use of this diagnostic algorithm. A score of 5 or higher indicates overt DIC, whereas a score of less than 5 does not rule out DIC but may indicate DIC that is not overt. Prospective validation studies show this scoring system to be highly accurate for the diagnosis of DIC. The sensitivity of the DIC score for a diagnosis of DIC is 91-93%, and the specificity is 97-98%.

Figure 1. Diagnostic Algorithm for The Diagnosis of Overt Disseminated Intravascular Coagulation

In clinical practice, a diagnosis of DIC can often be made by a combination of platelet count, measurement of global clotting times (aPTT and PT) and 1 or 2 clotting factors and inhibitors, and testing for FDPs.

Platelet count: typically, moderate-to-severe thrombocytopenia is present in DIC. Thrombocytopenia is seen in as many as 98% of DIC patients, and the platelet count can dip below 50 × 109/L in 50%. A decreasing treand in platelet counts or a grossly reduced absolute platelet count is a sensitive (though not specific) indicator of DIC. Repeated platelet counts are often necessary, a single platelet measurement may indicate a level within the normal range, whereas trend values might show a precipitous drop from previous levels.

Global clotting times: both aPTT and PT are typically prolonged. In as many as 50% of DIC patients, however, a normal or even an attenuated PT and aPTT may be encountered; consequently, such values cannot be used to exclude DIC. This phenomenon may be attributed to certain activated clotting factors present in the circulation, such as thrombin or Xa, which may in fact enhance thrombin formation.

It should be emphasized that serial coagulation tests are usually more helpful than single laboraatory results in establishing the diagnosis of DIC. It is also important to note that the PT, not the INR should be used in the DIC monitoring process. INR is recommended only for monitoring oral anticoagulant therapy.

DIC is associated with an unusual light transmission profile on the aPTT, known as a biphasic waveform. In one study, the degree of biphasic waveform abnormality had an increasing positive predictive value for DIC, independent of clotting time prolongation. In addition, the waveform abnormalities are often evident before more conventionally used laboratory value derangements, making this a quick and robust test for DIC.

Clotting factors: the prolongation of global clotting times may reflect the consumption and depletion of various coagulation factors, which may be further substantiated by the measurement of selected coagulation factors, such as factor V and factor VII.

Clotting inhibitors: protein C and antihrombin are 2 natural anticoagulants that are frequently decreased in DIC. There is some evidence to suggest that they may serve roles as prognostic indicators. Nonetheless, the practical application of measuring these anticoagulants may be limited for most practitioners the test may not generally available.

Fibrin: because fibrin is a central component of DIC, it would seem logical to assume that if soluble fibrin is elevated, the diagnosis of DIC can be made with confidence. However, soluble fibrin levels are not available to most clinicians within a relevant time fram.

Fibrinogen: the massive fibrin deposition in DIC suggests that fibrinogen levels would be decreased. Accordingly, measurement of fibrinogen has been widely advocated as a useful tool for the diagnosis of DIC; however, it is not, in fact, very helpful. Fibrinogen, as a positive acute-phase reactant, is increased in inflammation, and whereas values may decrease as the illness progresses, they are rarely low. On study demonstrated that in up to 57% of DIC patients, the levels of fibrinogen may in fact remain within normal limit.

Fibrin degradation products (FDPs): fibrinolysis is an important component of DIC; thus, there will be evidence of fibrin breakdown, such as elevated levels D-dimer and FDPs. D-dimer elevation means that thrombin has proteolyzed fibrinogen to form fibrin that has been cross-linked by thrombin-activated factor XIIIa. When fibrin becomes cross-linked insoluble, a unique D-D domain neoepitope forms. This cross-linked insoluble fibrin is then proteolyzed uniquely by plasmin to liberate the soluble D-D dimer. Thus, the D-dimer measures prior thrombin and plasmin formation. On the other hand, FDPs only inform that  plasmin has been formed and it cleaved soluble fibrinogen, fibrin, or insoluble cross-linked fibrin. D-dimer is the better test for DIC. However, FDPs are not used as often.

Thrombomodulin: This is the specialized test for DIC. Evidence suggests that serum levels of thrombomodulin, a marker for endothelial cell damage, correlate well with the clinical course of DIC, the development of multiple organ dysfunction syndrome (MODS), and mortality in septic patients. Thrombomodulin is elevated in DIC, and such elevation and not only correlates well with the severity of DIC but also can serve as a maker of early identification and monitoring of DIC.

Therapeutic Approach of Disseminated Intravascular Coagulation (DIC)

Treatment of DIC is controversial. Generally, the therapeutic approach consists of management of underlying disease, administration of blood components and coagulation factors, and restoration of anticoagulant pathways.

A DIC scoring system developed by Bick has been used to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities.[1] The scoring sytem is below (Table 2).

Table 2 Dic Scoring System by Bick

fibrinopeptide A in ng/mL< 30
3 – 101
11 – 402
41- 703
> 704
profragment 1,2 in nM0.2 – 2.70
2.8 – 5.91
6.0 – 7.42
7.5 – 10.03
> 10.04
D-dimer µg/L< 5000
500 – 1,0001
1,001 – 2,0002
2,001 – 2,9993
>= 3,0004
FDP (fibrin degradation products) in µg/mL< 100
10 – 401
41 – 802
81 –1203
> 1204
antithrombin (% of normal)85 – 125%0
75 – 84%1
65 – 74%2
54 – 64%3
< 54%4
alpha-2-antiplasmin (% of normal)75 – 120%0
65 – 74%1
55 – 64%2
45 – 54%3
< 45%4
fibrinogen in mg/dL150 – 3500
100 – 1491
75 – 992
50 – 743
< 504
platelet count per µL150,000 – 450,0000
100,000- 149,9991
75.000 – 99,9992
50,000 – 74,9993
< 50,0004
temperature in °C<= 29.94
30 – 31.93
32 – 33.92
34 – 35.91
36 – 38.40
38.5 – 38.91
39 – 40.93
>= 414
mean arterial pressure in mm Hg<= 494
50 – 692
70 – 1090
110 – 1292
130 – 1593
>= 1604
pulse rate in beats/minute<= 394
40 – 543
55 – 692
70 – 1090
110 – 1392
140 – 1793
>= 1804
Parameter (cont.)FindingPoints
respiratory rate per minute<= 54
6 – 92
10 – 111
12 – 240
25 – 341
35 – 493
>= 504
PaO2 in mm Hg80 – 1000
70 – 791
60 – 692
55 – 603
< 554
pH< 7.154
7.15 – 7.243
7.25 – 7.322
7.33 – 7.490
7.50 – 7.591
7.60 – 7.693
>= 7.704
creatinine in mg/dL< 0.62
0.6 – 1.40
1.5 – 1.92
2.0 – 3.43
>= 3.54
LDH in U/L<= 1930
194 – 2251
226 – 2502
251 – 2753
> 2754
albumin in g/dL3.5 – 5.50
3.0 – 3.41
2.6 – 2.92
2.1 – 2.53
<= 2.04
sodium in mEq/L<= 1104
111 – 1193
120 – 1292
130 – 1490
150 – 1541
155 – 1592
160 – 1793
>= 1804
potassium in mEq/L< 2.54
2.5 – 2.92
3.0 – 3.41
3.5 – 5.40
5.5 – 5.91
6.0 – 6.93
>= 7.04
hematocrit, in percent< 204
20 – 29.92
30 – 45.90
46 – 49.91
50 – 59.92
>= 604
total WBC count per µL< 1,0004
1,000 – 2,9992
3,000 – 14,9990
15,000 – 19,9991
20,000 – 39,9992
>= 40,0004


• 0 points is assigned to normal findings

• mean arterial pressure = [(systolic pressure) + (2 × (diastolic pressure))] / 3

• Since LDH shows some variability between laboratories, the LDH range can be rewritten: 0 points (<= 100% upper limit of normal); 1 point (> 100% ULN – 117% ULN); 2 points (> 117% ULN – 130% ULN); 3 points (>130% ULN – 142% ULN); 4 points (> 142% ULN)

DIC score = 100 – SUM(points for all parameters)

DIC scoreInterpretation
>= 90DIC unlikely
75 – 89mild DIC
50 – 74moderate DIC
< 49severe DIC


• maximum DIC score: 100

• minimum DIC score: 16


Underlying Disease

The management of DIC should primarily be directed at treatment of the underlying disorder. Often DIC component will resolve on its own with treatment. A DIC scoring system has been proposed by Bick to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities (Table 2).

Blood Components and Coagulation Factors

Typically, DIC results in significant reductions in platelet count and increases in coagulation times. However, platelet and coagulation factor replacement should not be instituted on the basis of laboratory results alone; such therapy is indicated only in patients with active bleeding and in those requiring an invasive procedure or who are otherwise at risk for bleeding complications.

Platelet transfusion may be considered in patients with DIC and severe thrombocytopenia, in particular, in patients with bleeding or in patients at risk for bleeding. The threshold for transfusion platelets varies. Most clinicians provide platelet replacement in nonbleeding patients if platelet counts drop below 20 × 109/L, though the exact levels at which platelets should be transfused is a clinical decision based on each patient’s clinical condition. In some instances, platelet transfusion is necessary at higher platelet counts, particularly if indicated by clinical and laboratory findings. In actively bleeding patients, platelet levels from 20 × 109/L to 50 × 109/L are grounds for platelet transfusion.

Previously, concerns have been expressed regarding the possibility that coagulation factor replacement therapy might “add fuel to the fire” of consumption; however, this has never been established in research studies.

It is generally considered that cryoprecipitate and coagulation factor concentrates should not routinely be used as replacement therapy in DIC, because they lack several specific factors (e.g., factor V). Additionally, worsening of the coagulopathy via the presence of small amounts of activated factors is a theoretical risk.

Specific deficiencies in coagulation factors, such as fibrinogen, can be corrected by administration of cryoprecipitate or purified fibrinogen concentrate in conjunction with fresh frozen plasma (FFP) administration.


Experimental studies have suggested that heparin can at least partly inhibit the activation of coagulation in cases of sepsis and other causes of DIC. However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has not yet been demonstrated in controlled clinical trials. Moreover, antithrombin, the primary target of heparin activity, is markedly decreased in DIC, which means that the effectiveness of heparin therapy will be limited without concomitant replacement of antithrombin.

Furthermore, there are well-founded concerns with respect to anticoagulating DIC patients who are already at high risk for hemorrhagic complications. It is generally agreed that therapeutic doses of heparin are indicated in cases of obvious thromboembolic disease or where fibrin deposition predominates.

Restoration of Anticoagulant Pathways

The antithrombin pathway is largely depleted and incapacitated in acute DIC. As a result, several studies have evaluated the utility of antithrombin replacement in DIC. Most have demonstrated benefit in terms of improving laboratory values and even organ function. However, large-scale randomized trials have failed to demonstrate any mortality benefit in patients treated with antithrombin concentrate.

Activated protein C (APC) is an important regulator of coagulation. In studies of patients with sepsis who had associated organ failure, APC has been shown to reduce mortality and improve organ function. Protein C concentrate has been used to treat coagulation abnormalities in adult patients with sepsis. A study found protein C concentrate to be safe and useful in restoring coagulation and hematologic parameters; however further study is required.

Tissue factor pathway inhibitor (TFPI) has been shown very promising to arrest DIC and to prevent the mortality and end-organ damage in animal studies. However, a large phase III trial of TFPI in human with DIC did not show any mortality benefit. Recombinant thrombomodulin (rTM) can be used for treatment of DIC in cases of severe sepsis and hematopoietic malignancy. rTM not only allows the conversion of protein C to APC, but also inhibits the inflammatory process by interacting with high-mobility group B (HBGM-1). rTM has shown beneficial effects on DIC parameters and clinical outcome in initial trials, which it was found to yield significantly improved control of DIC in comparison with unfractionated heparin, particularly with respect to the control of persistent bleeding diathesis.


1. Rodger L. Bick. Disseminated Intravascular Coagulation: Objective Clinical and Laboratory Diagnosis, Treatment, and Assessment of Therapeutic Response. Semin Thromb Hemost 1996; 22(1): 69-88.

The Management of Acquired Aplastic Anemia (Strategies)

June 6, 2013 Hematology, Pharmacotherapy, Therapeutics, Transplantation No comments , ,

Aplastic anemia is a disease in which the bone marrow, and the blood stem cells that reside there, are damaged. This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia).

Until the 1970s, severe aplastic anemia (SAA) was almost uniformly fata, but in the early 21st century most patients can be effectively treated and can expect long-term survival.


The pathophysiology responsible for marrow cell destruction and peripheral blood pancytopenia has itself been inferred from the results of treatment in humans, with substantial in vitro and animal model support.

The success of HSCT in restoring hematopoiesis in SAA patients implicated a deficiency of HSCs. Hematologic improvement after immunosuppressive therapy (IST) implicated the immune system in destruction of marrow stem and progenitor cells.

Genetics influences both the immune response and its effects on the hematopoietic compartment. There are histocompatibility gene associations with SAA, and some cytokine genes may be more readily activated in patients because of differences in their regulation, as suggested by polymorphisms in promoter regions.

An inability to repair telomeres and to maintain the marrow’s regenerative capacity, resulting from mutations in the complex of genes responsible for telomere elongation, has been linked to patients with familial or apparently acquired SAA, with or without the typical physical stigmata of constitutional aplastic anemia.

Approximately 5% to 10% of patients with SAA have a preceding seronegative hepatitis. However, most patients do not have a history of identifiable chemical, infectious, or medical drug exposure before onset of pancytopenia.

The antigen(s) inciting the aberrant immune response have not been identified in SAA. Furthermore, the current simple mechanistic outline may be supplemented in the future with better understanding of now theoretical possibilities, suggested by provocative murine models.

Management of Acquired Aplastic Anemia

Table 1. Criteria for SAA

For patients with moderate aplastic anemia, as defined by lack of blood count criteria for SAA, observation is often appropriate, especially when they do not require transfusion support. The criteria for SAA is in Table 1. Many of these patients may have stable blood counts for years, but in some pancytopenia worsens over time.

Once the disease progresses and the patients meets the criteria for SAA or become transfusion-dependent, treatment is always required. The therapeutic strategies for SAA include immediate supportive care, transplantation (HSCT), and immunosuppressive thearpy (IST), in which HSCT and IST are called definitive treatment.

Supportive care initiates and the definitive treatment should be started as soon as possible, since prolonged delay until initiation of primary treatment for SAA is not generally desirable and can result in serious complications before definitive therapy. Watchful waiting, especially if neutropenia is profound, can be harmful and is not appropriate once a diagnosis of SAA is confirmed. To realize this goal, it is prudent to rapidly assess whether matched sibling donors exist in the family for any patients younger than 40 years of age. Why the upper limit of age is 40 years is related to the risk of GVHD and we will discuss further below.

Immediate Supportive Care

Symptoms related to anemia and thrombocytopenia can be readily corrected with transfusions. Broad spectrum parenteral antibiotics are indicated when fever or documented infection occurs in the presence of severe neutropenia (< 0.5 × 109/L). As we have discussed in the blog “Platelet transfusion for patients with cancer (part two)“, prophylatic platelet transfusion is necessary when needed, and the threshold in these patients is 10 × 109/L.

Of note, transfusion of red cells aims to alleviate symptoms of anemia, not simply to target a specific hemoglobin threshold. Adequate red blood cell transfusions in symptomatic patients should not be deferred because of fear of iron accumulation or to reduce the risk of alloimmunization. However, in some guidelines it is recommended that starting iron chelation therapy in those patients who have received 20-25 units of packed RBCs or who have a serum ferritin level of >1000 μg/L (see post “The Management of Myelodysplastic Syndromes“).

In evaluating febrile neutropenic patients, simple chest X-ray is of limited value, so routine CT imaging of the sinus and chest is a preferred approach which followed by nasal endoscopy, bronchoscopy, and biospy for microbiologic confirmation when indicated. If fungal infection is suspected or neutropenic fever persists for more than several days despite broad-spectrum antimicrobials, empiric antifungal therapy should include drugs active against Aspergillus sp, as this pathogen has remained the most common fungal isolate in SAA patients for the past 20 years.

supportive measures alone, growth factors, androgens, or cyclosporine (CsA) are not definitive therapies. Patients should not be subject to initial trials of G-CSF or erythropoietin. Corticosteroids are of unproven benefit and inferior in efficacy to conventional immunosuppression regimens, but they are more toxic and should not be used as therapy in SAA. It is very unfortunate when a patient with SAA presents for transplant or IST but already has life-threatening fungal infection because of weeks or months of exposure to corticosteroids.

Figure 1. Algorithm for Initial Management of SAA

Algorithm for initial management of SAA


For malignancies, GVHD may offer graft-versus-tumor-benefits. For example, in AML the presence of GVHD is associated with reduced relapse of AML. However, in SAA GVHD is unequivocally to be avoided since the presence of GVHD in SAA definitely decreases survival and long-term quality of life.

The age of the patient with SAA is a crucial element for the decision to transplantaton. Generally, patient older than 40 years of age are not recommended to undergo transplantation since the correlation of increasing age with the increased risk of GVHD and therefore the significant morbidity and mortality of this complication is apparent. A study of more than 1300 SAA patients who were transplanted from 1991 to 2004 showed that survival at 5 years for patients younger than 20 years of age was 82%, for those 20 to 40 years of age 72%, and for those older than 50 years of age closer to 50%. Rates of GVHD increased with age, accounting for much of the decreased survival in older patients and the long-term morbidity.

The stem cell could be collected from either bone marrow or peripheral. The stem cell source also is important for survival and long-term quality of life. In a retrospective analysis, the rate of chronic GVHD was greater with peripheral blood (27%) compared with bone marrow stem cell grafts (12%) in patients younger than 20 years of age. In a subsequent retrospective analysis, similar higher rates of chronic GVHD were observed for patients of all ages undergoing HSCT with peripheral blood compared with bone marrow derived stem cell grafts.

For unrelated donor transplants, bone marrow source of stem cells was associated with lower rates of acute GVHD (31%) compared with peripheral blood-derived CD34+ cells (48%), which not only means bone marrow source is preferred than peripheral blood source but also matched sibling donor is preferred than unrelated donor.

The donor for HSCT consists of matched sibling donor and alternative donor. Again matched sibling donor is preferred since experience from larger cohorts reported in the last 5 years from the United States, Japan, Korea, and Europe suggests that the outcome with unrelated donor HSCT is still not as favorable as that of a matched sibling donor. Meanwhile, practically, identification of a matched unrelated donor and coordination with a transplant center usually takes several months, and delaying definitive IST while conducting a serach for nonfamily donor may be dangerous.

Prospective trials using umbilical cord HSCT in SAA are limited to smaller case series, which do show encouraging results. However, experience from larger cohorts in retrospective analyses indicate that overall survival is not as favorable as in pilots, at approximately 40% at 2 to 3 years. Graft rejection and poor immune reconstitution continue limit the success of umbilical cord HSCT.

Immunosuppressive Therapy

For patients older than 40 years of age, or yonger than 40 years of age but without matched sibling donor, IST is the first alternative therapeutic approach other than unrelated donor HSCT.

For patient older than 40 years of age, if initial IST fails (no response at 6 months, we define refractory SAA as blood counts still fulfilling criteria for severe pancytopenia 6 months after initiation of IST), we consider matched sibling HSCT first if he/she has a matched sibling donor. For patients younder than 40 years of age but without matched sibling donor, if initial IST fails, we conisider matched unrelated donor HSCT first if he has a histocompatible donor.

Whereas if the patient has no histocompatible donor or don’t suitable for HSCT we consider to repeat the IST therapy with rabbit ATG and CsA or with Alemtuzumab alone. If the patient remains no response 6 months after the second IST therapy, we consider HSCT (mismatched unrelated, haploidentical, or umbilical cord) or non-HSCT approach (see in Figure 1).

Standard initial IST is horse ATG (anti-thymocyte globulin) and CsA (cyclosporine), which produces hematologic recovery in 60% to 70% of cases and excellent long-term survival among responders, as shown in several large prospective studies in the United States, Europe, and Japan.

The mechanism of action by which polyclonal antilymphocyte preparations suppress immune responses is not fully understood. Possible mechanisms by which Thymoglobulin may induce immunosuppression in vivo include: T-cell clearance from the circulation and modulation of T-cell activation, homing, and cytotoxic activities. Thymoglobulin includes antibodies against T-cell markers such as CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA-DR, HLA Class I heavy chains, and ß2 micro-globulin. In vitro, thymoglobulin (concentrations >0.1 mg/mL) mediates T-cell suppressive effects via inhibition of proliferative responses to several mitogens. In patients, T-cell depletion is usually observed within a day from initiating Thymoglobulin therapy. Thymoglobulin has not been shown to be effective for treating antibody (humoral) mediated rejections.

Study showed the addition of CsA to ATG increased the hematologic response rate, however, other agents such as mycophenolate mofetil, growth factors, or sirolimus to horse ATG/CsA did not improve rates of response, relapse, or clonal evolution. A more lymphocytotoxic agent rabbit ATG, has been successful in salvaging patients with refractory or relapsed SAA after initial horse ATG. But in recent large, randomized controlled study, hematologic response to rabbit ATG (37%) was about half that observed with standard horse ATG (68%), with inferior survival noted in the rabbit ATG arm. Therefore horse ATG remains the most effective regimen for first-line IST therapy regimen of SAA.

Therapy Response Evaluation

We use simple definition for hematologic response: no longer meeting blood count criteria for SAA, which closely correlates with transfusion independence and long-term survival. Hematologic improvement is not to be expected for 2 to 3 months after ATG. The majority of response (90%) occur within the first 3 months, with fewer patients responding between 3 and 6 months or after.

After ATG therapy patients with SAA needed to long-term follow-up, we will discuss this scope in another post. Coming soon.