Nutritional Anemias

India has the largest number of anemic persons worldwide, and common etiologies are nutritional deficiency of iron, folic acid, and vitamin B12 in descending order of frequency. The National Nutritional Anaemia Prophylaxis Programme (NNAPP) was started in 1972 for iron and folic acid supplementation to pregnant women and children. Screening for anemia, iron–folate therapy, and route of administration for prevention and management of anemia was incorporated. The national prevalence of IDA in children younger than 5 years, women 15 to 49 years, and pregnant women are 75%, 51%, and 87%, respectively. Estimates on maternal deaths from anemia/year are 22,000, which contribute to 20% to 40% of maternal deaths and low birth weight. Anemia increases susceptibility to infections, reduced work capacity, and poor concentration. The National Rural Health Mission was launched in 2005 to educate mothers on health and nutrition in villages. Despite continued efforts, anemia continues to be a major problem affecting all population strata ( http://www.mohfw.nic.in ).

Plausible reasons include adverse effects of iron pills, improper utilization of health service, and personal beliefs. Poor iron (<20 mg/d) and folic acid intake (<70 μg/d), poor bioavailability of iron (3%–4%) in a phytate fiber-rich Indian diet, and chronic blood loss due to malaria and hookworm infestations contribute to continued high prevalence of IDA. Oral iron therapy is useful, as ferrous ascorbate and intravenous colloidal preparations are reserved only after inadequate response to oral preparation.

Thalassemias and Hemoglobinopathies

These constitute a heterogeneous group of autosomal-recessive disorders caused by globin gene defects causing quantitative reduction (thalassemias) or qualitative defects (hemoglobinopathies) in globin chains. Thalassemias are classified based on defective globin chain, as α-thalassemia, β-thalassemia, δ-thalassemia, and. Symptomatic hemoglobinopathies include sickling syndromes like homozygous HbS, HbS/BTT, and rarely HbS/HbD Punjab. Double heterozygosity of HbE with beta thalassemia causes symptomatic thalassemia syndrome in eastern states.

Identification of asymptomatic β-thalassemia traits (BTT) has led to screening of partners and offered prenatal diagnosis to at-risk pregnancies. Hypochromic microcytosis with raised red blood cell count is encountered in BTT and α-thalassemia trait. The diagnostic hallmark of BTT is HbA2 of between 4% and 8%, which remains normal (2.2%–3.5%) in α-thalassemia trait. The national average frequency of BTT is 3.5% (range 0.3%–15%) and greater than 10,000 infants affected with TM are born each year. Estimates of α-thalassemia traits are limited, because DNA-based molecular tests are required. The average frequency ranges from 12.5% in the general population to 78.4% in endogamous tribal population. Management of TM includes 3 weekly blood transfusions and iron chelation. Currently, 3 centers are offering bone marrow transplantation (BMT) to TM patients nationally.

Molecular analysis to detect causative mutations for β-thalassemia shows regional differences. There are 64 mutations reported nationally, and the most common 5 traits, namely IVSI-5(G→C), 619 bpdel, IVSI-1(G→T), Codon 41/42(-TCCT), and Codon 8/9(-G) account for 82.5% of alleles. Uncommon mutations like Codon 15(G→A), Codon 30(G→C), Cap+1(A→C), Codon 5(-CT), and Codon 16(-C) account for an additional 11% of mutations. Ten centers perform prenatal diagnosis for reducing the burden of TM.

Other Anemias

ACD is encountered because of disorders like tuberculosis, rheumatoid arthritis, and chronic renal failure. ACD causes increased morbidity and can coexist with IDA. Serum ferritin with soluble transferrin receptor (sTfR/log ferritin ratio) levels can distinguish between ACD and IDA; however, few laboratories perform sTfR. Physicians need to distinguish these disorders to decide treatment with iron supplementation or erythropoietin. Genetic hemolytic anemias like G6PD deficiency are common and present as neonatal hyperbilirubinemia or sporadic infection-related hemolysis. Hereditary spherocytosis, sideroblastic anemia, and congenital dyserythropoieticanemias are seen uncommonly. Recently, homozygosity mapping revealed a founder SEC23B –Y462C mutation in Indian CDA type II patients. Acquired anemias include aplastic anemia, paroxysmal nocturnal hemoglobinuria, and pure red cell aplasia, but there are no documented epidemiologic studies to indicate that the frequencies are different to the West.

Hereditary Hemochromatosis

Hereditary hemochromatosis, a common genetic disorder in the West, is rare in Indians. Low index of suspicion and a high prevalence of IDA could contribute to late presentation of the disorder. The HFE gene mutation c.845G→A; p.C282Y, which accounts for 90% to 95% of cases in Northern Europeans, is absent in Indians. Recently, the authors have found novel mutations in the hemojuvelin gene ( HJV ; Barjinder Kaur, Reena Das, unpublished 2013), and private mutations have been reported from Pakistan and Bangladesh.

Inherited Coagulation Disorders

Hemophilias (HA and HB) are the most common inherited bleeding disorders. The Hemophilia Federation India, a nongovernment organization, was established in 1983 and has 76 chapters and provides data on bleeding disorders. In 2013, there were 16,800 registered HA patients, compared with 3000 in 2003. The registry is incomplete, and most patients are registered from west India. India reported 462 vWD cases and 458 cases with platelet function disorders and rare coagulation factor deficiencies. Among the latter, data from 54 hemophilia treatment centers showed FXIII (30%) to be the most common deficiency, followed by deficiencies of FX (15.6%), FVII (15%), and fibrinogen (12.1%). Automation in coagulation in referral hospitals has made tests standardized and reproducible.

Confirmatory tests for vWD (eg, von Willebrand Factor antigen assay, Ristocetin Cofactor assay, and multimer analysis) are available in specialized laboratories, leading to inaccurate diagnosis of type 2vWD. The Indian Society of Hematology and Blood Transfusion and the Christian Medical College, Vellore run an External Quality Assessment Scheme (EQAS) program for hemostasis with more than 100 participants. Prenatal diagnostic facilities for hemophilias are available nationally in five centers.

Qualitative Disorders of Platelets

Platelet function analyzers and aggregometers are not in common use, and therefore the estimates for qualitative disorders of platelets are inaccurate. Bernard Soulier Syndrome and Glanzmann thrombasthenia are uncommonly encountered. Confirmatory flow cytometry has facilitated early diagnosis but is restricted in availability.

Management of Bleeding Disorders

The chronic nature of the bleeding disorders requires comprehensive care involving replacement of deficient coagulation factor, preventing further bleeds, reducing disability, orthopedic support, and rehabilitation programs including psychosocial support to the family. Suboptimal management is reflected by presentation with joint deformities. Currently only 16 of 29 Indian states provide free FVIII and IX replacement to patients during a major bleed (on-demand situations). In other states, patients are dependent on fresh frozen plasma or cryoprecipitate. Financial constraints limit prophylactic replacement therapy. Plasma-derived factor products available are Immunate P and Immunine, whereas, recombinant factors available are Recombinate and Advate. There exists a large gap between the recommended 1 IU/capita usage of FVIII for optimal survival and the available 0.023 IU/capita. Bleeds in vWD are managed with 10 to 20 IU/kg of FVIII concentrates or 1 to 2 cryobags/10 kg weight. Supportive therapy includes topical tranexamic acid (30–40 mg/kg/d) for oral mucosal bleeds or epistaxis. Desmopressin is used in mild vWD with minor bleeds and menorrhagia. Females with vWD require hormonal preparations for regulating menstruation and iron supplementation. Use of rest, ice, compression, and elevation is beneficial and inexpensive supportive therapy. Need for compliance with hormonal therapy for control of ovulation may be overlooked with disastrous consequences. Indian patients have been managed with lower doses of FVIII replacement (35 IU/kg preoperatively and 10–20 IU/kg postoperatively in major surgery) without undue excess of serious bleeding in the setting of major and minor surgical procedures. Development of inhibitors is less frequent in Indians, possibly due to late initiation of replacement therapy. Inhibitors were seen in 6.07% of 1285 HA patients, with highest frequencies from South India (20.99%). Activated prothrombin complex concentrates and recombinant FVII are needed, but the high cost becomes a limiting factor. Immune tolerance is rarely attempted.

Thrombotic Disorders

Hospital-based studies on medical patients and postoperative surgical situations are available on the prevalence of deep vein thrombosis (DVT) and pulmonary embolism (PE). The DVT rate in a retrospective study from South India was 17.46 cases per 10,000 admissions, with 64% of cases in nonsurgical settings. A north Indian study found the incidence of DVT as 2.7/1000 person–days of hospital stay in medically ill patients with grade 1 to 2 mobility. Compression ultrasonography and color Doppler imaging are used for the diagnosis of limb DVT. Angiography, MRI and D-dimer assay are available. Risk factors like factor V Leiden (FVL; G1691A) mutation, deficiencies of protein C, S and antithrombin, and antiphospholipid antibodies are encountered. The prevalence of FVL ranges between 3% and 20% in patients with thrombosis at various sites. In contrast to the western population, prothrombin mutation G20210A is absent.

For thromboprophylaxis, unfractionated heparin is popular because of the low cost of therapy. The low molecular weight heparins (LMWH) available in India are dalteparin, enoxaparin, nadroparin, fondaparin, parnaparin, and fondaparinux. Monitoring of LMWH is mostly empirical, because anti-Xa assay is largely unavailable. The oral anticoagulants available are warfarin and acenocoumarol. Close monitoring of dosage is challenging, as point-of-care instruments are sparsely available. Becuse Indians are predominantly vegetarian, high consumption of green leafy vegetables can lead to variation in anticoagulant effect of the drugs, and good patient education and counseling are required. Experience with the newer anticoagulants is limited.