Hematology

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Humoral immune compromise

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Types:
- defect in B cells: MM, splenectomy (important in antigen recognition), common variable immunodeficiency (insufficient Ab production), X-linked agammaglobulinemia
- defect in antibody response: multiple myeloma
Associated Infections:
- encapsulated organisms: S. pneumonia, H. Influenza, N. meningitides

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Cell-mediated immune compromise

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Types:
- T-cell destruction: HIV (CD4s), glucocorticoids, immunosuppression (solid organ transplant), lymphoma (Hodgkin’s)
- loss of T-cell function: inability of CD8’s to recognize MHC-1 or CD4’s to recognize MHCII
Associated infections:
- CD8 cells target intracellular pathogens, while CD4’s target phagocytosed antigen
- organisms w/ intracellular phase: viruses, mycobacteria, listeria, Cryptococcus, toxoplasma, chlamydia
- Pneumocystis (not intracellular)

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Innate immune compromise

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Types:
- neutropenia: usually due to cytotoxic chemo (90%)
- pancytopenia: bone marrow failure (acute leukemia, myeloproliferative diseases)
- neutrophil dysfunction: Chronic Granulomatous Disease (congenital inability to form ROS), decreased neutrophil activation
Associated infections:
- susceptible to extracellular pathogens: bacteria, yeasts (candida), opportunistic molds (ex: Aspergillus)

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Late effects of cancer

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= unrecognized toxicities of neoplasms and treatments that are absent or subclinical at the end of therapy and manifest later
Late effects of childhood cancer: growth impairment, physical impairment, gonadal dysfunction, infertility, offspring complications, subsequent malignancy, caridotoxicity, pulmonary dysfunction, neuropsychologic problems, psychosocial problems, live dysfunction, thyroid dysfunction, GI dysfunction
Development of subsequent cancers:
- risk increases w/ time from diagnosis. Hodgkin’s (9.4x) and bone tumor were most at risk
- types: breast (23%), thyroid (16%), malignant CNS (10%)
Gonadal failure:
- acute ovarian failure (never menstruating or ceasing menstruation 5y after dx). 6% of pediatric cancers, 54% of which received >100cGy radiation to ovaries (dose dependent >2000cGy : 171x risk). Alkylating agents provarbazine (2.6x) and cyclophosphamide (5x) also associated
- male infertility (no barriers to siring children, trying for 1 year). Directly related to radiation dose/alkylating agent use
All treatments for cancer (chemo, radiation, surgery) are correlated to Late Effects. Multiple treatments make it more complicated. When choosing therapy consider: age at dx, sex (females more sensitive), genetic of individual/tumor risk, social factors, comorbidities, lifestyle, etc.
Long Term Follow Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers: provides risk factors, potential effects, and follow-up guidelines for different therapies. Many healthcare centers now have survivorship clinics

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Cancer survivorship

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From the time of diagnosis and for the balance of life, a person diagnosed with cancer is a survivor. This expansive definition of "survivor" includes people who are dying from untreatable cancer. NCCS later expanded the definition of survivor even further to include family, friends and voluntary caregivers who are affected by the diagnosis in any way. According to the American Cancer Society, there are now more than 13.7 million cancer survivors in the United States. That number is expected to grow to nearly 18 million by 2022.

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Complications of hyperleukocytosis

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= WBC >100,000, usually AML, ALL
Before treatment: (AM: >200K)
- sludging, CNS injury from cerebral hemorrhage or thrombosis, pulmonary leukostasis (looks like ARDS)
After treatment: tumor lysis syndrome (ALL >300K)
- renal failure, electrolyte abnormalities
-Tx: hydration, maintain platelet level at 50K (risk of DIC), exchange transfusion (replace blood volume w/ new blood, 80cc/kg, may cause low Ca)

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Typhilitis

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= bacterial overgrowth of the intestine occurring due to myelosuppression from chemo
- classically in cecum & appendix
Complications: increased risk of sepsis, GI obstruction, GI bleed, GI perforation w/ pneumatosis (air) in bowels. Often correlates to mortality after induction chemo (not necessarily cause)
Presentation: LRQ abdominal pain usually, but any abd pain should be suspicious
Management:
- broad spectrum abx (gram+, gram-, anaerobic coverage): meropenum + vancomycin
- monitor for DIC, manage constipation/diarrhea, pain, and nutrition

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Complications of mediastinal masses

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= masses that arise from lymphoproliferative diseases from enlargement of immune organs
Airway compression:
- occurs at or below vocal cords: intubation may be ineffective
- complete obstruction must be cleared in 5min.
- signs: tripod position, use of accessory muscles, cough, dyspnea, orthopnea, hoarseness, wheezing (not always asthma—should evaluate)
Superior vena cava syndrome:
- mass compresses SVA reducing blood return from upper circulation
- can cause failure to adequately perfuse the cerebrum, clotting/PE (from venous stasis), upper extremity/head edema, altered mental status
- tx: maintaining airway patency, biopsy w/o sedation, chemo/radiation to eliminate mass

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Spinal cord compression in leukemia

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= compression of the spinal cord by chloroma (mass of white cells)
Presentation: back pain (>90%), decreased peripheral pain sensation, increased reflexes, sensory or rectal tone changes, reduced sexual/urinary/rectal function
At risk cancers: sarcoma, neuroblastoma, leukemia/lymphoma
Dx: clinical syndrome (pain localization), imaging
Tx: surgical removal of affected discs/tumors, chemo/radiation to reduce mass effect. Worse prognosis with longer symptoms

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Febrile neutropenia

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= development of fever while neutropenic, indicating infection (while severely immunocompromised). Typically complication of chemo myelosuppression
Organisms: pseudomonas (from gut, ↑mutation/resistance rate), staph & strep (gram+ cocci, oral and skin flora), anaerobes (located in mouth, GI, abcesses), yeast/molds (found in mouth, skin)
Management: hospitalization for all peds cases, risk stratification low/high risk to determine administration of fungal/antibiotic coverage
Stratification:
- low (patient): solid tumors, ALL or NHL in remission (after first 28d), neutropenia <7d, neutropenia expected <10d
- high (patient): active ALL/NHL, AML, sepsis (chills), mouth sores, focus of infection
- low (infection): gram- from enteric source (ex: pseudomonas). Tx: ceftazadime
- High (infection): gram+ from mouth or skin (ex: staph, strep), pseudomonas in high risk patient. Tx: Ceftazadine
- High + abdnominal symptoms (infection): abscesses (oral, perirectal), anaerobes. Tx: meropenum & vancomycin.
- unstable: frank sepsis (hypotension, tachycardia, respiratory distress, pallor, sick appearing). Concern for SPACE (Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter/Enterococcus). Double coverage abx: meropenum, vancomycin, amikacin

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Tumor lysis syndrome

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= complication of cancer treatment due to large scale lysis of tumor cells
Pathogenesis: high turnover of cells due to chemotherapy results in large release of DNA (converted to uric acid), phosphate (can bind free blood calcium), potassium (normally low extracellularly).
Complications: ↑K (cardiac arrhythmias: peaked T waves, sin waves), ↑phos (renal failure),↓Ca (muscle spasms, seizures, heart failure), ↑uric acid (renal stones, failure). Infection can increase cell lysis
Tx:
- Always IV fluids at 1.5-3x maintenance to prevent uric acid stones, calcium urate and calcium phosphate stones
- Allopurinol: decrease serum uric acid (block xanthine oxidase preventing conversion). Rasburicase also can be used (dissolves uric acid, does no block enzyme)
- Amphogel: binds phosphorus in gut to reduce absorption
- Urine acidification can prevent phosphate stones, but can stimulate uric acid stones
- Hydration, diuretics, and dialysis if severe renal failure. Renal insufficiency usually corrects, so dialysis is not permanent

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Monoclonal B-cell lymphocytosis

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= precursor B-cell proliferation to CLL
- asymptomatic patients with CLLs , but <5000/mcL so do not meet the diagnostic criteria for CLL
- as patients ages, CLLs accumulate and normal B-cell function declines
Epi: found in 1% of asymptomatic adults <40, 5% >60

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Myeloma spectrum classification

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Monoclonal gammopathy of undetermined significance (MGUS)
- Serum monoclonal protein <30 g/L AND
- Clonal plasma cells <10% on marrow biopsy AND
- No myeloma-related organ or tissue impairment (CRAB)
Asymptomatic (smoldering) myeloma
- Serum monoclonal protein 30 g/L AND/OR
- clonal plasma cells >10% on marrow AND
- No myeloma-related organ or tissue impairment (no CRAB)
Symptomatic myeloma:
- monoclonal protein in serum or urine AND
- clonal plasma cells >10% on marrow AND
- myeloma-related organ or tissue damage (CRAB: hyperCalcemia, Renal insuffiency, Anemia, Bone lesions (lytic or osteoporosis w/ compression fractures)

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International Prognostic Scoring System for MDS

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Prognostic variables:
- Bone marrow blasts: <5% (0), 5-10% (0.5), 11-20% (1.5), 21-30% (2)
- cytogenetics: good (del(20q), del(5q)) (0), intermediate (0.5), poor (-7, >3 abnormalities) (1)
- cytopenic lineages: 0/1 (0), 2/3 (0.5)
Risk:
- low (0): median survival 5.7y, 25% transform to AML in 9.4y, primary therapeutic goal is improvement of ineffective hematopoiesis, reduction in iron overload
- Intermediate I (0.5-1)
- Intermediate II (1.5-2): median survival 1.2y, 25% transform to AML in 1.1y
- High (>2.5): median survival 0.4y, 25% transform to AML in 0.2y, goal of therapy is to delay transformation to AML, extend survival

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Myelofibrosis (w/ myeloid metaplasia)

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= advanced stage myeloproliferative disorder of stroma causing fibrous replacement of the marrow space
Pathophys: collagenous replacement of marrow space impairs hematopoiesis resulting in pancytopenia. Precursor cells will migrate away from the marrow resulting extramedullary hematopoiesis (liver, spleen)
Presentation: anemia, splenomegaly +/- hepatomegaly, bone pain, bruising/bleeds, fatigue, infection, pallor, dyspnea
Dx: pancytopenia, smear w/ teardrop and immature cells. Marrow is scarred (“dry tap”), hypercellular

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Essential thrombocytosis

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= myelodysplastic disorder of overproduction of megakaryocytes/platelets
Pathogenesis: unknown, some a/w JAK2 kinase mutations
Presentation: bleeding (epitaxis, gums, GI), thrombosis (burning in extremities from occlusion), splenomegaly
Dx: platelets >450,000/mcL in absence of other cause (Fe deficiency, chronic inflammation, other MPD’s), JAK2 mutation if present
Prognosis: may progress to polycythemia vera or AML. W/ treatment usually well controlled
Tx: hydroxyurea (to reduce platelets), aspirin, pegylated interferon

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Polycythemia vera

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= myelodysplasic disorder causing increased production erythrocytes (primarily), megakaryocytes, and granulocytes (panmyelosis)
Pathogenesis: mutated JAK2 (V617F) increases response to EPO (despite low serum levels) and other cytokines. At advanced stages may produce blood in liver/spleen
Signs (usually related to hyperviscosity, sludging, thrombosis): dyspnea, orthopnea, bleeds (gums, GI, ecchymoses), erythromelagia, pruritis, splenomegaly, PUD
Dx: Hb >18.5/16.5 gm/dL, low epo, ↑WBCs, platelets

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Myeloproliferative diseases/neoplasms (MPD/MPN)

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= low grade malignancies arising from myeloid lineage precursors in the bond marrow which produce excess myeloid cells
Complications: hepatosplenomegaly, cytopenia, myelofibrosis
- related to myelodysplastic syndrome, may progress to AML, though MPD has better prognosis
Pathogenesis: AGT alteration results in mutated JAK tyrK causing increased sensitivity to cytokines and growth factors.
Treatment: JAK2 inhibitors (Ruxolitinib) for advanced stage, pegylated interferon to suppress abnormal hematopoiesis in mild cases
Types: CML, polycythemia vera, essential thrombocytosis, myelofibrosis (w/ myeloid metaplasia

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Myeloid Hemopathies

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= diseases that arise from disruption of the normal functions of myeloid cells
Self-renewal:
- Aplastic anemia: marrow does not produce enough new cells, results in pancytopenia
Proliferation: often disordered when gene hybridizing results in activation of tyrosine kinase receptors
- CML: BCR-ABL produces hyrbrid TyrK
- polycythemia vera, essential thrombocythemia, myelofibrosis: JAK2 activation results in increased sensitivity to erythropoietin causing expansion of myeloid compartments
Differentiation:
- AML: arrest of maturation results in proliferation and preservation of blasts
Apoptosis:
- MDS: increased cell death (due to dysmorphogenesis) causes cytopenia
- CML: BCR-ABL inhibits apoptosis through Bcl2

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HIV NH lymphomas

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- increased incidence of all lymphomas: 100x
- increased incidence of Burkitt and plasmablastic lymphoma (both high grade)
- increased grade of other lymphomas: DLBCL, described as “Burkett-like”
- now increased cure rate (50-60%) when using chemo + anti-retrovirals (can’t use chemo alone- can’t tolerate

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Infectious associated w/ lymphoma

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Hepatitis C : splenic marginal zone lymphoma (indolent- treat infection)
H. Pylori : MALToma (indolent, treat infection)
Mycosis Fungiodies: Mature T cell Lymphoma involving the skin (persistent/slowly progressive disfiguring skin lesions varying size/shape)

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International Prognostic Index (IPI)

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= prognostic module for diffuse large B-cell lymphoma at diagnosis
All Patients : Risk factors
- Age : >60y
- Performance status : 2-4 (1= symptoms, 2= some limitation, 3= bed ½ day, 4 = full bed rest, 5 = dead)
- LDH level : elevated
- Extranodal involvement : >1 site (not included if <60y)
- Stage : III-IV
Risk: low (0-1, 85%), Low-intermediate (2, 75%), high-intermediate (3, 50%), high (4-5, 50%)
Age adjusted (w/o age, extranodal): L 1, LI 2, HI 3, H 4

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Grading NHL

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Indolent/low grade:
- decreased apoptosis
- presentation: diffuse lymphadenopathy, more likely to involve marrow
- Tx: observation +/- chemo
- prognosis: mnths/yrs/decades of survival w/o treatment, Incurable
- ex: follicular lypmphoma (grand I and II)
Aggressive/Intermediate grade:
- decreased apoptosis, increased mitosis
- Tx: combination chemo as an outpatient
- prognosis: wks/mnths survival w/o treatment, >50% cured
- ex: diffuse large B-cell lymphoma, follicular lymphoma (grade III)
Very aggressive/high grade
- decreased apoptosis, very increased mitosis
- Tx: combination chemo as inpatient w/ intensive supportive care
- prognosis: dys/wks survival w/o treatment, >50% curable
- ex: Burkitt’s lymphoma, precursor B lymphoblastic lymphoma

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Non-Hodgkin Lymphoma

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= all lymphomas (B & T cell) that are not Hodgkin’s (very diverse)
- majority are B cell 80-85%, heterogeneous presentation and course. 4% of all malignancies, rising
Risk: ↑age (peak 50-60), exposures (unknown, pesticides, herbicides, solvents, organics, dusts, hair dye), immune suppression: iatrogenic (chemo, radiation, transplant, AI treatment), inherited (Wiskott Aldrich, common variable immune deficiency, autoimmune lymphoproliferative syndrome), infectious (HIV/AIDS: 100x), autoimmune disorders (RA, Sjogrens, Hashimoto’s , Celiac), infectious (human T lymphotroic virus -1, EBV, herpes 8, Hep C, H. pylori)

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Hodgkin’s Lymphoma

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= B-cell lymphoma w/ lymphatic spread
Epi: 7/100K, bimodal incidence (20’s, late life), M=F early but M>F late
Risk: HIV (20x, though < NHL), iatrogenic immune suppression, EBV exposure (esp. late), high socioeconomic status (germ exposure related?)
Presentation:
- lymph: asymmetric contiguous lymphadenopathy (firm/rubbery, supraclavicular fossa), rare liver/spleen or extranodal involvement
- constitutional: 1/3 B symptoms (fever, night sweats, weight loss, fatigue), pruritis, pain when drinking alcohol
- autoimmune: cytopenia (ITP, AIHA)
- immunodeficiency: zoster, not complete suppresson
Histo Subtypes: nodular sclerosing, lymphocyte predominant (rare), mixed cellularity
Dx: biopsy: Reed-sternberg cells (transformed post-germinal B cells, often have EBV transcripts) in nodes on excisional biopsy (need usually not sufficient), CBC (↑LDH, ↑ESR, HIV, chemistries)
Staging (PET/CT, BM biopsy): Ann Arbor: I. 1 lymph region, II. 2 lymph regions, III. Lymph above/below diaphragm, IV: disseminated. E if extranodal at any level.
Prognosis: w/o treatment fatal 1-3y (mass effect, infections, anemia), w/ treatment: I >90%, II 90%, III 85%, IV 75%
Tx: local (XRT +/- chemo), disseminated (combined chemo: ABVD (Adriamycin, bleomycin, vincristine, dacarbazine) or others (BECOPP, Stanford VI, MOPP). Relapse <1y HSCT. Long term follow-up for 2nd malignancies, CAD

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Lymphoma

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= malignancy arising from the cells of the lymphatic system (mature/near-mature B and T cells)
- primarily lymph nodes (may be internal/non-palpable), but also spleen, MALT, marrow. >75% are B cell in origin. Share characteristics w/ the cell type it’s derived from
- HL has contiguous spread (lymphatic), while NHL is sporadic (hematogenous)
- Ann Arbor staging: I 1node group, II >2 node groups, III node groups on either side of diaphragm, IV disseminated and extranodal. E: extranodal at I-III (s if spleen)
Clinical manifestations:
- painless swelling of lymph nodes in the neck, occiput, axilla, or groin
- “B symptoms”: fever, night sweats, weight loss, fatigue
- others: ETOH induced pain at node, itch skin, reddened patches on skin

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Complications of stem cell transplant

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Pre-engraftment:
- common: severe myelosuppression (neutropenic fevers, sepsis), GI toxicity (N/V, mucositis, anorexia)
- uncommon: renal toxicity, liver toxicity, pulmonary hemorrhage, CMV
Post-engraftment:
- GVHD: acute (rash, diarrhea, jaundice) and/or chronic (join inflammation, skin sclerosis/rash)
- others: EBV induced lymphoproliferative disease, myelodysplastic syndrome, solid tumors

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Chronic myeloid leukemia

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= single chromosomal abnormality causing proliferation of myeloid cells without arrest in maturation, resulting in excess of all myeloid lineages (myeloproliferative neoplasm)
Pathogenesis: balanced translocation (9,22) resulting in juxtaposition of BCR-ABL. ABL (9) is a non-receptor tyrosine kinase oncogene, BCR (22) is involved in signal transduction. BCR-ABL controls adhesion, apoptosis, cell signaling, and proliferation pathways.
Presentation: mostly ASx, ↑WBC (always), hepatosplenomegaly (usually advanced stage), early satiety syndrome (weightloss),
Phase: chronic (asymptomatic, 4-6y survival), accelerated (symptomatic, 1yr survivial), blastic phase (conversion to AML, 3-6m survival)
Dx: CBC (leukocytosis), PBS (leukocytosis of all myeloid lineages/maturation state), marrow (hypercellularity), genetics (identify Ph+: karyotype, FISH, PCR)
Tx: Targeted therapy (Imatinib, dasatinib, Nilotinib) binds ATP binding site in tyrosine kinase. Can provide a cure for some, some resistance developing. Transplant if failure

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Acute myeloid leukemia

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= arrest in differentiation and clonal proliferation of myeloid precursors
Epi: 1/150K cancers, bimodal distribution (20’s, 80’s)
Risks (most idiopathic): benzene, radiation, Down’s, Fanconi anemia, chemotherapy (alkylators, topoisomerase II inhibitors), heme diseases (CML, MDS)
Presentation:
- non-specific (reflect cytopenia, organ infiltration): fatigue, dyspnea, palpitations, roaring in ears, fever, infections, bruising, bleeding, bone pain, hyperviscosity (mental status/vision changes, dyspnea), chloromas (bruising)
- exam: pallor, petechiaes, ecchymosis, splenomegaly, lymphadenopathy, gingival hyperplasia, skin nodules, perirectal abscess
Dx:
- CBC (↑WBCs, ↓RBCs/platelets), PBS (blasts w/ Auer rods), biopsy (hypercellularity, granular blasts, myeloid specific staining (myeloperoxidase, non-specific esterase))
- immunophenotype: myeloid (CD13, 33, 117, HLA-DR)
Prognosis: (WBCs @ presentation, age, disease subset, LDH, initial response)
- good (>60% w/ chemo alone): t(15,17)--promyelocytic, t(8,21), Inv 16
- poor (require transplant): ch -5, -7, +8, complex cytogenetics
- intermediate/normal karyotype: stratify w/ FLT3-ITD, others
Tx (eradicate blasts, re-establish normal hematopoiesis): induction (anthracycline, AraC), response stratification, consolidation (high dose AraC), observation or transplantatio

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Lymphopenia DDx

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= low lymphocyte count
Ddx:
- immunodeficiency
- autoimmune disease
- steroid use
- viruses
- left shift (relative increase in segmented neutrophils)

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Neutropenia ddx

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= low neutrophil count
Risks:
- < 1500: neutropenic (not necessarily bad since 80% of neutrophils stored in marrow—as long as reserve is there)
- < 750: mild risk of infection
- < 500: moderate risk of infection
- < 200: severe risk of infection
DDx:
- autoimmune destruction
- splenomegaly: sequestration/destruction
- marrow suppression
- drugs
- viral infection

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Leukopenia DDx

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= low WBCs
DDx:
- ethnic variation: AA often have lower, standards are for Caucasians
- viral infections
- drugs (multiple mechanisms)
- margination
- immune deficiency
- autoimmune process
- sepsis
- malignancy
Work up: evaluate individual cell ines

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Thrombocytopenia + anemia DDx

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= low platelets and low RBCs
DDx:
- Evan’s syndrome (AIHA + ITP): immune destruction of RBCs and platelets
- Bleed secondary to ITP: thrombocytopenias make you prone to bleeds, usually GI
- Primary marrow disease (affecting 2 cell lines): AML, ALL

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Thrombocytopenia DDx

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= reduction in normal platelet count. Usually acquired due to increased destruction. Rarely decreased production due to congenital abnormalities
- large platelets on smear often indicates increased destruction
DDx:
- DIC: disseminated intravascular coagulation, extra clotting is using up platelets
- TTP: thrombotic thrombocytopenic purpura
- HUS: hemolytic-uremic syndrome
- ITP: immune thrombocytopenic purpura

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Pancytopenia

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= decrease in two or more hematopoietic (CBC) cell lines. Typically due abnormal cell development in the marrow (cancer, infection, AI, etc)

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Pre-malignant hematological conditions

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= derangement of hematopoiesis to produce abnormal cells that are not yet malignant (missing some characteristics of malignancy)
Myelodysplastic syndromes: disordered maturation leading to dysmorphic cells (nuclear/cytoplasmic asynchrony). Apoptosis is intact (prevents malignancy) resulting in low cell counts.
Myeloproliferative syndromes (CML, essential thrombocytosis, polycythemia vera): proliferation advantage and loss of apoptosis result in excess production and preservation of otherwise normal cells (very high cell counts, splenomegaly)

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4 basic processes leading to malignancy

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Loss or gain of function: loss occurs in tumor suppressors (usually 2 mutations), gain occurs in proto-oncogenes (1 mutation). (ex: most cells in ALL are non-functional, so pt immunocompromised despite lymphoid excess)
Genes/pathways/cells no longer function in intended role
Growth advantage: a mutation must confer competitive survival advantage over other cell lines (ex: p53 mutations remove cell cycle regulation)
Impaired apoptosis: must evade normal cellular mechanisms for controlling aberrant cells. (ex: Bcl-2, anti-apoptosis gene, up-regulated in Ph+ chromosome)
Ability to spread: more important for solid tumors (cross membranes, angiogenesis)

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Lymphoid vs. Myeloid systems

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Lymphoid: hematopoietic lineage of cells derived from pleuripotent stem cell producing T/B/NK cells (lymphocytes)
- Differentiation and replication no limited to the marrow (occurs in lymph tissue). Allows for different cancer types depending on character/location of cell at time of mutation
- potentially unlimited life span (plasma cells)
- defects in development mat effect: marrow and lymph tissue (thymus, nodes)
- multiple DNA slices during lifespan (incl VDJ recombination)allows for cancer-causing mutations/splicing errors
Myeloid: hematopoietic lineage of cells derived from pleuirpotent stem cell producing blood cells and components of the innate immune system
- all differentiation occurs in the marrow (circulating cells are fully differentiated)
- short life span outside of the marrow (48hrs for PMN)
- defects in development affect the marrow
- no changes to DNA occur in lifecycle (errors are incorporated at earlier replicative stages)

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Candidiasis

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= endemic yeast
Epi: naturally growing GI yeast, seen most in GI patient post surgery
Risks: neutropenia, indwelling lines, hemodialysis, diabetes, AIDS, abdominal surgery, critical illness, colonization, neonate or >65y, recipient of TPN, broad spectrum antibiotic
Presentations:
- UTI: dysuria, polyuris, +/- pyuria. Treat if symptomatic, if not only treat if immunocompromised, at extremes of age, undergoing GU surgery
- pneumonia: uncommon
- mucocutaneous: oral thrush, esophagitis, diaper rash, chronic mucocutaneous (T-cell deficit, nail or skin infections), vaginitis, folliculitis, ungal, angular chelitis
- operative site: hepatosplenic abscess
- bloodstream: prevents as sepsis: fever, shock, positive cultures
Dx: culture, tissue histopathology, glucan antigen test

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Terbinafine

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= azole antifungal
Mechanism (PO/topical): binds ergosterol forming pores in the cell membrane
Spectrum: dermatophytes, some endemics
Elimination: renal, hepatic metabolism
Side effects: GI upset, ↑LFTs, liver failure

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Posaconazole

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= azole antifungal
Mechanism (PO): binds ergosterol forming pores in the cell membrane
Spectrum (widest): yeasts, molds, endemics, also zygomycetes
Elimination: fecal, metabolized by UDP system (glucoronidation), no dose adjustment for liver/renal failure
Side effects: ↑LFTs, GI upset, many drug interactions (tacrolimus, sirolimus, midazolam)

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Voriconazole

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= azole antifungal
Mechanism (IV/PO): binds ergosterol forming pores in the cell membrane
Spectrum: yeasts (candida, crypto, coccidiodes), some molds (aspergillus**, fusarium, dimorphics, penicillium)
Elimination: hepatic via CYP450 (CYP3A4), no adjustment for renal failure but don’t use IV if CrCl <50mL/min
Side effects: potent inhibitor of CYP450 (many drug interactions), ↑LFTs, altered vision, hallucinations, GI upset

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Fluconazole

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= azole antifungal
Mechanism (IV/PO): inhibits ergosterol synthesis, disruption cell membrane integrity
Spectrum: yeasts (candida, crypto, coccioides)
Elimination: renal (dose must be adjusted for renal dysfunction), metabolized by CYP450
Side effects: GI upset, LFT increase, minimal drug interactions

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Echincandins (IV)

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Ex: caspofungin, micafungin, anidulafungin
Mechanism: inhibit glucan synthetase (resides in cell membrane, constructs cell wall)
Spectrum: yeasts (candida), molds (aspergillus), should not be given in isolation
Elimination: hepatic w/ little metabolism
Side effects (minimal): ↑LFTs, ↓Hb, ↓platelets

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5-fluorocysteine (oral)

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- anti-fungal (among other uses)
Mechanism: converted to 5-FU which is incorporated as a nucleotide stopping RNA synthesis → cell death
Spectrum: yeasts (candida, crypto), some dematiaceous molds
Elimination: renal, dose must be adjusted for renal failure
Side Effects: bone marrow suppression, GI upset, ↑LFTs

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Azoles

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Ex: fluconazole, voriconazole, posaconazole, terbinafine
Mechanism: inhibits ergosterol synthesis, distruption cell membrane integrity
Spectrum: yeasts (candida, crypto, coccidoides), some yeasts are resistant
Elimination: renal, dose must be adjusted for renal dysfunction
Side effects: liver injury (↑LFTs), drug interactions (so cross-over inhibition of human CYP450s)

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Polyenes

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Ex: amphotericin B (systemic), nystatin (typically topical)
Mechanism: binds ergosterol in cell membrane forming pores and ion leakage → cell death
Spectrum: most yeasts and molds
Elimination: hepatic and renal, no change in dosing for renal failure
Side effects: nephrotoxicity, infusion reaction (shakes/rigors, chills, HTN, fever), lab abnormalities (↓K, ↓Mg, ↓Hb). Lipid formulation of amphotericin have decreased toxicity and can be pushed to higher doses

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Types of fungi

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Yeasts:
- genus: candida (systemic – echinocandins, mucocutaneous topical azole), cyptococcus (disseminated – amphotericin B + flucytosine, pulm – Azoles), sacromyces
- morphology: round w/ budding daughter cells (candida may form pseudo-hyphae—narrow at septa)
Molds:
- genus: aspergillus (voriconazole +/- echinocandin), fusarium, zygomycetes/mucorales (amphotericin B, posaconazole)
- morphology: from hyphae w/ parallel walls, no narrowing between septa
Dimorphics:
- genus: histoplasma, blastomyces, coccidioidomyces, sporothrix
- morphology: yeast form (higher/body temps) and mold form (ambient temps)

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RDW index

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= describes range of red cell size (range of approximate bell curve where MCV is the mean width)
Calculation: (standard deviation of MCV/mean MCV) x 100
Normal: 11-15%
Abnormal:
- high (anisocytosis, indicates multiple RBC populations, use MCV to see which dominates): iron deficiency anemia (low MCV), folate/B12 deficiency (high MCV), hemorrhage (normal MCV)

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MCH/MCHC index

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MCH
= the average amount of hemoglobin per RBC
Calculation: MCH = Hb/RBC
Normal: 27-31 pg/cell
MCHC
= the average concentration of Hb in each RBC
Calculation: Hb/Hct x 100
Normal: 32-36 g/dL
Abnormal:
- high (hyperchromatic): hereditary spherocytosis, sickle cell, homozygous Hb C disease
- low (hypochromatic): microcytic anemias

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MCV index

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= mean corpuscular volume (RBC size).
- used to differentiate between macro and micro-cytic anemia
Calculation: MCV = Hct x 10/RBC
Normal: 80-99 fL
Abnormal:
- high: hemolytic anemia (excess reticulocytes), macrocytic anemia, vitamin B12/folic acid deficiency
- low: iron deficiency, thalassemia, sideroblastic anemia, chronic disease, cancer (low MCV + guiac+ = GI malignancy)

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RBC index

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= total number of RBCs per volume
Normal:
- men: 5-6 million/microliter
- women: 4-5 million/mcL
Abnormal:
- high: polycythemia vera (excess RBC production), COPD/ischemia, blood doping, capillary leak syndrome
- low: hemorrhage, iron deficiencies, chronic kidney disease

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HCT index

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= proportion of blood volume occupied by RBCs. Usually around 3x [Hb]
Normal:
- Men: 45%
- Women: 40%
Abnormal:
- high: polycythemia vera (excess RBC production), COPD/ischemia, blood doping, capillary leak syndrome
- low: hemorrhage, iron deficiencies, chronic kidney disease

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Hb index

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Normal:
- Men: 13.8 – 18 g/dL
- Women: 12.1 – 15.1 g/dL
- Children: 11 – 16 g/dL
Abnormalities:
- High: high altitudes, dehydration, smoking, tumors
- low: anemia, loss of blood, nutritional deficiencies, bone marrow problems, chemotherapy, kidney failure, abnormal hemoglobin

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Hemoglobin catabolism

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- Hb is toxic if free (causes vasoconstriction, has no allosteric regulation, loses redox capacity).
Mechanism: old/defective RBCs phagocytosed by reticular endothelial system in spleen and liver. Globin chains then recycle to amino acids, Fe is bound to transferrin and reutilized, heme oxygenase and biliverdin reductase covert heme to bilirubin and bile
If there is increased heme desctruction, first will see a rise in unconjugated/indirect bilirubin

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Sickle Cell anemia

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= common hemoglobinopathy, characterized by sickling of erythrocytes
Epi: 8-10% in AA’s, >30% in Africa
Genetics: HbS has replacement of valine for glutamate in 6th codon of β chain. When deoxygenated HbS polymerizes, forming rigid, needle-like fibers that precipitate in the RBC (exacerbated by dehydration, acidosis, high temp)
Complications: chronic hemolysis, microvascular occlusions/infarction causing tissue damage (lungs, kidney, bones, liver, skin, brain → stroke, paralysis, renal failure), extreme pain (from infarction, ulcers, bone degeneration), increased infection severity (P. pneumonia, H. flu, N. meningitides)
Other variants: HbC (lysine for glutamine at 6, common in C. W. Africa), HbE (lysine for glutamine at 26, SE Asia). Cause milder anemias, significant if combined with other defects
Dx: Hb electrophoresis (detect HbS)
Tx: hydroxyurea (DNA synthesis inhibitor→ ↑HbF, anti-inflammatory),
Prognosis: 98% now reach adulthood

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Hemoglobin disorders

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Hemoglobinopathies: genetic defects leading to structural defects in Hb molecule, non-enxymatic protein
- methemoglobins: metHb containing oxidized Fe3+ (rather than Fe2+), lower O2 affinity
- unstable hemoglobin: decreased functionality or increased sensitivity to oxidative stress. Incl: sickle cell, congenital dyserythropoietic anemia
Thalassemias: mutations causing decreased or dysfunctional synthesis of α or β Hb chains
Porphyrias: defects in porphyrin synthesis affecting hemoglobin, myoglobin, cytochromes
- congenital erythropoietic porphyria, erythrohepatic protoporphyria, acute intermittent porphyria (recurrent abdominal pain, neurologic symptoms, liver damage), porphyria cutanea tarda, and mixed porphyria

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Hemoglobin

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Structure:
- 4 polypeptide globin chains, most commonly 2α, 2β
- 4 heme porphyrin heme molecules with O2-binding iron
Properties:
- solubility: Hb A can dissolve, ↑blood O2 carrying capacity by 70x (O2 not real soluble in blood)
- cooperative O2 binding: (tight/deoxygenated → relaxed/oxygenated) binding of first O2 induces conformational change making second binding more favorable. O2 dissociation curve not linear: more binding exponentially increases saturation curve
- allosteric modification (increases range of oxyhemoglobin saturation): 2,3 BPG can bind Hb causing right sift/dissociation. Low pH, CO2, Cl-, higher temp also favor dissociation

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Neutrophilia

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= increase in neutrophil count due to increased production, increased marrow release, or defective margination.
- can accompany almost any cause of inflammation, especially bacterial/fungal infection and cancer
Main Mechanisms:
1. Reactive (response to infection): G-CSF mediated increase in neutrophil production + release. ↑WBC detectable in as little as 4-6h post initiation of infection
2. Malignancy or myeloproliferative disorder
3. Post-splenectomy: increased due to loss of granulocyte trap (platelets also increased)

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Absolute neutrophil count (ANC)

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= WBC/mcL x (%segs + % bands)/100
Normal > 2000/mcL
African subset >1500 mcL
Inversely related to the risk of major infection with bacteria and fungi
- 500-1000mcL = mild increase in risk
- 100-500mcL = moderate increased risk, control of endogenous microbial flora impaired
- <100mcL = greatly increased risk of infection, loss of local inflammatory process

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Granulocytopenia/neutropenia

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= absolute neutrophil count (ANC) < 2000/mcl, or african subset <1500
Mechanism:
- Decreased production: most common, results from use of cytotoxic or immunosuppressive therapies for malignancy/AI disease or some antibiotics and antiretrovirals. Drugs cause dose-related marrow suppression (inhibit stem cell production), cessation usually leads to reversal. Other causes: hematologic diseases (aplastic anemia, Chediak-Higashi, etc), tumor invasion of the marrow, myelofibrosis, nutritional deficiency (B12, folate), infection (TB, HIV, malaria, others)
- Increased cell loss: autoimmune due to circulating anti-neutrophil antibodies (RA, SLE, Feity’s syndrome), acquired due to viral infection (including HIV) drugs, granulomatosis
- Increased sequestration in spleen (also effects RBCs, platelets, and other granulocytes)
- increased margination: rare, increased adherence to vascular endothelium (so not free in blood to be counted) as occurs prior to extravasation or increased migration to tissues. May occur due to overwhelming bacterial infection (acute endoxemia)

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Hereditary hemolytic anemias

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= inherited abnormalities in RBC membrane, hemoglobin, or metabolism causing hemolysis due to trapping in spleen, liver, and microvasculature due to spherocytosis, abnormal shape, decreased deformity, increased phagocytosis by macrophages (may be secondary to damage or primary). Trapping in capillaries can cause obstruction and ischemia.
Inherited membrane abnormalities:
- hereditary spherocytosis: protein abnormality causes sphere formation, membrane budding, increased Na+ permeability. AD or AR, most common hemolytic anemia of N. Europeans. Present w/ compensated anemia, microspherocytes, ↓MCV, ↑MCHV, negative Coomb’s, increased lysis w/ hypotonic NaCl solution
- hereditary elliptocytosis: defective membrane protein. Common in AA’s, present w/ mild anemia, ↑retics, diagnostic smear
Inherited Hemoglobinopathies: due to amino acid substitutions into globin changes causing distortion of shape, decreased deformability/filterability, membrane damage/stiffening
- sickle cell: homozygous substitution of valine for glutamic acid on β chain, 1/400 in AA’s. Present: PAIN, ↑retic, ↓Hb, sickled cells and Howell-Jody bodies on smear. Dx: hemoglobin electrophoresis, positive solubility test
- Hemoglobin S-C disease: heterozygous for HbS/C, 1/800 AA’s. Present: mild anemia, ↓/Norm Hb, similar smears to Sickle w/ prominent target cells and Hb crystals. Dx: Hb electrophoresis, positive solubility test
- Hemoglobin C disease: mild anemia and abdominal pain, ↓MCV, target cells, C-crystals on smear, Hb electrophoresis
- Sickle trait: 8% of AA’s, occasional hematuria, renal concentrating defect, sickle carrier state
- congenital Heinz body: amino acid substitutions destabilize Hb causing Heinz body formation
Inherited Enzymes deficiencies: result in poorly functioning enzyme, enzyme instability, combination
- G6PD-deficiency: X-linked, predisposes lysis by oxidating substances and Heinz body formation (hemolytic anemia following drug/infection/fava bean challenge). A- type (15-20% of AA’s, causes instability), Mediterranean type (unstable and poor functioning).
- Embden-Meyerhof Pathway abnormalities: rare cause of non-spheroctytic anemia due to ↓ATP. Incl: pyruvate kinase deficiency, hexokinase deficiency

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Immune-positive causes of acquired hemolytic anemia

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= Coomb;s positive hemolysis caused by antibody or complement attachment to RBC membrane
Alloimmune:
- transfusion related when antigen is transfused into a recipient with antibodies. May cause immediate acute transfusion reaction or (more common) delayed transfusion reaction (7-14 days. Suspect if Hb falls to pre-transfusion levels and new Ab present).
- Uncommonly free antibodies in plasma can be directed against host RBCs
- Erythroblastosis fetalis: caused by transplacental transfer of maternal antibodies against fetal RBCs
Autoimmune: antibodies against components of RBC membrane (mostly extravascular)
- IgG: almost exclusive splenic hemolysis. Usually warm-reacting +/- complement binding. May be second to: lymphoproliferative syndromes, SLE, collaged vascular diseases, other tumors, idiopathic. Labs show hemolytic anemia, microspherocytes, positive Coomb’s (IgG +/- complement). Tx: steroids and splenectomy
- Complement: usually hemolysis in the liver and intravascular space. Cold-reacting
- IgM: cause intravascular and hepatic hemolysis, usually cold-reactive, bind complement (Coomb’s is complement positive only). May be secondary to viral and mycoplasma infections, lymphoproliferative disease, idiopathic in elderly. May also have Raynaud’s and other vaso-occlusive disorders. Labs: hemolysis, anemia, hemoglobinuria, hemogio-binemia, microspherocytes and agglutination. Tx: steroids/splenectomy not effective, treat underlying cause, supportive care, immunosuppression for idiopathic
Drug Induced:
- hapten/penicillin type: drug adheres to RBC membrane followed by IgG Ab. Only high dose IV penicillin. Coomb’s IgG only positive
- innocent bystander: Ab-drug complex passively adheres to RBC membrane enabling complement binding. Incl: quinidine, chlorpromazine, sulfonamides. Coomb’s complement only positive
- Aldomet type: drug induces formation of autoantibody to Rh+ RBC by inhibiting T-suppressor activity. 15% of aldomet patients, 1% have hemolysis. Coomb’s IgG only positive.

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Non-Immune causes of Acquired Hemolytic anemias

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= Coomb’s negative disorders resulting from acquired abnormalities to the erythrocyte environment causing shortened survival
- hypersplenism (splenomegaly): due to infection, portal HTN, infiltrative leukemia/lymphoma, collagen vascular disease. Frequently pancytopenia w/ hypercellular marrow, splenic sequestration.
- Fragmentation (microangiopathic): mechanical, intravascular destruction of RBCs, may cause hemosiderinuria. See schistocytes, no platelets. Causes: fibrin strands, platelet plugs, abnormal endothelium, prosthetic valves and patches, severe valve disease, aortic coarctation, DIC, TTP, small vessel vasculitis, malignant HTN and eclampsia, disseminated carcinomas, hemangiomas, ateriovenous fistulas.
- physical/chemical agents: osmotic hemolysis (IV water, freshwater drowning), 3rd degree burns (heat damage to membranes), arsine gas
- lipid abnormalities: (overload leads to spur cell formation) abetalipoproteinemia, severe liver disease
- Infectious agents: intra-erythrocyte parasites (malaria, babesiosis—lyse cells on exit), Clostridium perfringens septicemia (α-toxin creates membrane pores)
- Hypophosphatemia (< 0.5mg/dL): perhaps due to ATP depletion (see spur cells). Seen in alcoholics, re-feeding syndrome, recovery from DKA
- nocturnal hemoglobinuria: intrinsic abnormalities in membranes very sensitive to hemolysis by complement.

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Hemolytic anemia

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= anemias resulting from RBC loss in circulation. Characterized by ↑retic production (>75k, >3% corrected) w/ falling or stable Hb (anemia may not always be present if compenstated)
Findings: ↑indirect bilirubin (destruction of RBCs), ↑LDH, hemoglobinemia, hemoglobinuria, ↓serum haptoglobins, hemosiderinuria, erythroid hyperplasia, decreased RBC survival (as measured by Cr51 radiolabeling)
Extrinsic/Acquired: resent onset of signs/symptoms (normal previous blood draws). Result from
- non-immune (Coomb’s negative): hypersplenism, fragmentation (microangiopathic), physical/chemical agents, lipid abnormalities, infectious agents, hypophosphatemia, paroxysmal nocturnal hemoglobinuria
- Immune (Coomb’s positive): alloimmune, autoimmune, drug-induced
Congenital:
- inherited membrane abnormalities: hereditary spherocytosis, hereditary elliptocytosis
- inherited hemoglobinopathies: sickle cell, hemoglobin S-C disease, hemoglobin C disease, sickle trait, congenital Heinz body
- inherited enzyme deficiencies: GSPD deficiency, Embden-Meyerhof Pathway abnormalities

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Folate deficiency

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= macrocytic megaloblastic anemia due to impaired DNA synthesis (identical to B12- on smear, ddx w/ history)
- normally reduced to dihydrofolate and tetrahydrofolate which is methylated to donate and convert dUMP to dTMP
Hx: alcoholism, diet lacking in fresh fruits/vegies (elderly poor).
Symptoms: weakness, fatigue, dyspnea, paresthesias
Signs: stigmata of alcoholic liver, edema, pallor, jaundice, smooth tongue. Nor neurological involvement
Normal requirements: 50μg (average diet contains 700, only 10% absorbed, 5-10 stored)
Causes: alcoholism, deficient diet, increased requirements (chronic hemolytic anemia, pregnancy, peritoneal dialysis, chronic infections, exfoliative dermatitis), small bowel disease/resection, congenital absence or iatrogenic inhibition of polyglutamate deconjugation enzymes (dilantin, estrogens/OCPs), deficient interconversion to tetrahydrofolate (liver disease, B12 deficiency, folate inhibitors—methotrexate)
Dx: ↑homocysteine, ↓serum and RBC folate, low or normal B12

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B12 deficiency

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= macrocytic megaloblastic anemia due to impaired DNA synthesis. Usually autoimmune (pernicious anemia)
- B12 is cofactor for the conversion of homocystine to methionine. Deficiency causes accumulation of 5-methyl tetrahydrofolate (can’t participate in DNA synthesis)
Epi: rare, usually malabsorption (requirements 1μg/d, body stores 2-5), Symptoms: weakness, fatigue, dyspnea, paresthesias, mental clouding
Signs: edema, pallor, jaundice (lemon yellow), smooth/atrophic tongue, angular stomatitis, decrease vibratory and positional sensation, peripheral neuropathy, corticospinal tract findings, subacute combined neural degeneration (due to demyelination)
Causes: breast fed infants of vegans, pernicious anemia (autoimmune lack of intrinsic factor for gut absorption, 70%), small bowel disease (nontropical sprue, regional enteritis, Celiac), surgical bowel resection, parasites (fish tapeworms or bacteria compete for dietary B12), drug inhibition (para-aminosalicytic acid, colchicine), rare inherited malabsorptive disorders (absence of ileal receptors, inactive IF secreted), impaired transport (lack transcobalamin II—only responsive to massive B12 doses)
Dx: ↓B12, ↑homocysteine/methylmalonate (also in Folic acid deficiency), ↑urinary excretion of methylmalonic acid (v. specific), variable folate, megaloblastic anemia. If pernicious will correct w/ intrinsic factor administration (Schilling Test), autoantibodies. Or documentation of malabsorption
Tx: exogenous B12 injections

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Megaloblastic Anemias

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= macrocytic anemia resulting from inhibition of DNA synthesis in RBC production (cell cannot progress from G2 growth state to mitosis causing continued growth w/o division)
Labs: ↑MCV, ↑RDW, ↓retic (precursors are fragile), ↓Hb, ↑LDH, ↑indirect bilirubin, ↑Fe/transferrin sat, neutropenia, thrombocytopenia
Smear: macro ovalocytes, hypersegmented PMNs, large platelets, leukoerythrocyte reaction (early release from marrow)
Marrow: hypercellular, megaloblastic
Etiologies:
- B12/Folate deficiency
- drug or inherited inhibition of DNA synthesis
- erythroleukemia

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Macrocytic anemias

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= anemia w/ MCV > 94 μL (inadequate cell division or problems w/ DNA synthesis)
Causes:
- ↑ retic counts: see lots of immature cells, should mature in 48-72hrs becoming normocytic
- liver disease, obstructive jaundice, postsplenectomy (loss of terminal processing: may see nucleated RBCs, howell-jolly bodies): cause excess lipids in cell membrane, target cells
- hypothyroidism: increased lipid membranes, no target cells (normal smear)
- megaloblastic anemias (DNA synthesis insufficiency): B12 deficiency, folate deficiency, drug or inherited inhibition of DNA synthesis, erythroleukemia). Immature chromatin pattern (lots of euchromatin), ↑RDW, marrow megaloblasts, peripheral ovalocytes, hypersegmented PMNs. May also have neutropenia, thrombocytopenia w/ large platelets

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Microcytic anemia

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= anemia w/ MCV < 80 fL, usually associated with disordered hemoglobin synthesis
Etiologies:
- iron deficiency: inadequate iron
- chronic inflammation: may be concurrent w/ iron deficiency
- thalassemia: defective Hb synthesis/function
- sideroblastic anemia: mitochondrial damage results in defective protoporphyrin synthesis

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Normocytic anemias

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= MCV between 80 and 94 μL and normochromic normocytic RBCs on peripheral smear
Causes: (increased RBC or damaged marrow limiting supply)
- acute blood loss: most common cause w/ ↓retics. Must be eliminated first in all anemia evaluations
- Expanded plasma volume: pregnancy (30% expansion), cardiac or renal failure (erythropoietin deficiency), fluid overload, nephrotic syndrome
- endocrine disorders: hypothyroidism (reduced tissue O2 requirements → ↓erythropoiesis), adrenal failure (has lymphocytosis and eosinophilia, corrects w/ steroids), gonadal dysfunction in males (androgens increase erythropoietin production and effects—estrogen will suppress this)
- chronic renal disease (CrCl <50 mL/min): decrease in erythropoietin production, shorten RBC survival, increased blood loss. (symptoms usually blunted due to ↑O2 delivery/2,3BPG from metabolic acidosis/hyperphosphatemia)
- Marrow Failure: aplastic anemia (erythroid hypoplasia w/ preservation of other elements; congenital or acquired—thymoma, Parvo B19), leukemia
- Marrow replacement (myelophthistic anemia): infection, tumor, granuloma, fibrosis, leukemia. Causes tear-drop shaped RBCs, leuko- or erythro-blastic reaction (early white/red cell in circulation)
- Anemia of chronic inflammation: associated w/ abnormal iron metabolism

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α-Thalassemia

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= disorder of α-globin chain synthesis causing microcytic hypochromatic anemia
- Epi: SE Asia, Mediterranean, Africa, African Americans.
Genetics: phenotype determined by deletion of mutation of 1-4 copies of α-genes (2/chromosome)
Types:
- Hydrops Fetalis (0 functional α-genes): no production of normal hemoglobin (only Barts-γ4) resulting in insufficient O2 transport, splenomegaly, hypertrophied placenta, enlarged heart, and fetal death at 34-40wks due to heart failure
- Hemoglobin H disease (1 of 4 functional): elevated Bart’s Hb at birth and Hb H later in life. Clinically variable, most resemble β-thalassemia intermedia (severe anemia, non-trasfusion dependent, splenomegaly). Labs: ↑retics, microcytic hypochromatic cells (+/- target) w/ Hb H inclusions, Hb H/Barts on electrophoresis
- minor (2 of 4 functional): ↓MCV +/- mild anemia. Electrophoresis normal in adults, elevated Barts/microcytosis at birth (5-10%). Deletion almost always trans in Africans (so more severe disease forms rare)
- silent (3 of 4 functional): hematologically normal (1-4% Bart’s at birth), carrier state

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β-Thalassemia

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= disorder of β-globin chain synthesis, resulting in microcytic hypochromatic anemia
- Epi: high frequency in Mediterranean area, Southeast Asia, Africa
- β-globin DNA is present, but mRNA is not produced or translated normally
Major: homozygous defects resulting no (β0) or severely decreased (β0β+) globin synthesis causing severe, transfusion-dependent anemia (ineffective erythropoiesis and hemolysis)
- Presentation: severe anemia, jaundice, and hepato-splenomegaly in first year of life. Secondarily: growth retardation, frequent infections, skeletal changes, iron overload w/ skin pigmentation, cardiac decompensation, endocrinopathy.
- Prognosis: early death even with transfusion support
- Labs: severe microcytic hypochromatic anemia w/ target cells and basophilic stippling, normoblasts and ↑retics, ↑ Fe/%sat/ferritin. ↓HbA, ↑HbA2, ↑/N HbF
Minor: heterozygous mutations leading to mild anemia and microcytosis +/- splenomegaly. Targeting and basophilic stippiling in peripheral smear, ↑HbA2 and HbF
Intermedia: complex inheritance pattern causing severe anemia w/o transfusion dependence

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Types of hemoglobins

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HbA: 2α, 2β; major hemoglobin of normal RBCs
HbA2: 2α, 2δ, 2-3% in adults
HbF: 2α, 2γ; major hemoglobin of fetal RBCs, <1% in adults
HbH: 4β; occurs in severe α-thalassemia
Bart’s: γ4; occurs in severe α-thalassemia

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Thalassemias

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= microcytic hypoproliferative anemias due to inherited disorders of globin chain synthesis (most common global monogenetic disorders)
- disorders cause decreased normal mRNA of either α or β-globin leading to deceased production of HbA (and anemia) and production of other hemoglobins
Dx: ↑erythrocyte count w/ ↓MCV and normal ferritin
Types:
- β: decreased β-globin production leading to relative increase in δ, γ-globins and HbA2, HbF
- α: decreased α-globin, resulting in production of Hb H (β4) and Hb Bart’s (γ4)

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Anemia of chronic inflammation

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= normocytic or microcytic (more severe) hypoproliferative anemia that accompanies conditions of chronic inflammation (>6w): long-standing infections (TB, syphilis, abcess), neoplastic disease, RA, SLE, gout
- Pathogenesis: macrophage/monocyte activation and production of IL-1, IL-6, TNF stimlulating hepcidin, which prevent Fe transport out of macrophages and shortened RBC survival. Defective re-utilization of iron after cell lysis: iron release to plasma is blocked, so it accumulates in the reticuloendothelial system
- patients may also have iron deficiency anemia (makes disease more severe)
Symptoms: mild, usually just manifestations of underlying disease
Lab: mild anemia (9-11gm/dL), ↓retics, norm/↓ MCV, mild microcytosis on smear. ↓Fe, ↓transferrin, ↓transferrin saturation, ↑ferritin (high total body iron). Marrow: ↑RES storage, reduced/absent sideroblasts
Tx: control of underlying disease, epo given but questionable benefit

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Iron deficiency anemia

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= microcytic hypoproliferative anemia due to prolonged loss of iron in excess of absorption.
- Daily requirements: 1mg males/non-menstruating females, 2 for menstruating females, 3-4 for pregnant women. Bleeding causes 0.5mg/mL loss whole blood.
- Most is in Hb but significant % circulates bound to Ferritin. Uptake from the gut regulated/inhibited by hepcidin (binds to ferroportin)
Etiologies:
- increased loss (90%): GI bleed (60%), excessive menstrual bleeding (30%)
- decreased iron intake: deficient diet (20%), iron malabsorption (15%)
- Increased iron requirement: pregnancy (6%), lactation (<1%)
- unknown mechanism (17%)
Symptoms: weakness, fatigue, dyspnea, pallor, tachycardia, glossitis, angular stomatitis, pica, koilonychia (nail spooning)
Lab findings: ↓retic, ↓MCV, ↓MCHC. ↓Fe, ↑transferrin, ↓transferrin saturation
Smear: Hypochromatic, microcytic cells
Tx: identify source of iron deficiency/loss, exogenous iron administration

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Hypoproliferative anemias

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= anemia w/o appropriate increase in reticulocytes
Causes: destruction or replacement of marrow, lack of substrate for erythropoiesis, suppression of erythropoiesis, decreased stimulation of marrow
Types:
- microcytic (MCV <80): from reduced heme synthesis (iron, porphyrin, or globulin). Iron deficiency, chronic inflammation, sideroblastic, thalassemias

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Reticulocyte count

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= proportion of reticulocytes to mature RBCs
- corrected count differentiates between anemia due to decreased production (low) vs. increased loss (high)
Normal: 0.5 – 1.5%
Abnormal:
- High (increased RBC production): hemolytic anemia, hemorrhage
- low (destruction/loss of precursors/hematopoietic response): chemotherapy/radiation, aplastic anemia, erythropoietin synthesis defects, dietary deficiency, disease states
Variations:
- corrected Retic (to account for anemic state): Raw Retic % x HCT/45
- Absolute retic: Raw retic % X RBC count
Anemia:
- hypoproliferative: corrected Retic <2% or Abs Retic <75,000/μL
- hemolytic: correctic Retic >2% or Abs retic >75,000/μL

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Anemia

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= decrease in hemoglobin resulting in impaired tissue oxygenation (usually Hb or HCT <2 SD below mean)
Types: (assess with retic to see if marrow is responding appropriately)
- hypoproliferative: insufficient/ineffective RBC production, retic <1%
- hyperdestructive: excess loss of RBCs in peripheral circulation, retic >2%

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Cells of the bone marrow

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Stem cells:
- undifferentiated progenitor cells with potential for differentiation into multiple lineages (myeloid or lymphoid). CD34+, CD38-, kit+, Thy+, Lin-
- self-renewing (can replicated w/o differentiating), most are quiescent (G0 phase of mitosis), rare in marrow (1/100k marrow cells)
Progenitor cells:
- defined by ability to form colonies in tissue culture in semi-solid media (agar, methyl-cellulose)
- limited self-renewal, occur in 1/1000 marrow cells
- differentiation guided by cytokines in response to systemic needs (infection, etc): promote early lineage specific development, enhance survival of specific lineages, drive proliferation into that lineage, promote differentiation, and activate or prime differentiated cells
Differentiated myeloid cells:
- leukocytes, RBCs, neutrophils, monocytes, eosinophils, basophils, platelets

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Granulocyte maturation

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Myeloblast (earliest identifiable precursor): immature cell w/ large, oval nucleus, sizable nucleoli, few to no granules, high nucleus/cytoplasm ratio
Promyelocyte (second precursor cell): defined by presence of primary (azurophilic) granules in the cytoplasm
Early/late/meta/band-myelocytes: secondary granules specific to final cell type are synthesized and accumulate. Differentiation occurs
Myelocytes (neutrophils, eosinophils, basophils): terminally differentiated, enter marrow pool or are released into circulation (for a few hours before entering tissue). 90% of total body myelocytes stored in the marrow (10-day supply), ready to be released in response to infection. Average circulation time of a neutrophil is 10hrs w/ turnover 2.5x/day

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Erythrocyte maturation

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Develop from myeloid stem cells and progenitor cells.
Progression: proerythroblast, basophilic erythroblast, polychomatophilic erythroblast, orthochromatophilic erythroblast (last nucleated stage), erythrocyte

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Platelet maturation

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Develop from myeloid stem cells and progenitor cells
Differentiation involves continuouos replication w/o cell division (endomitosis), resulting in megakaryocytes w/ as much as 218N DNA. At final stage cytoplasm is partitioned into cytoplasm and released into the blood
Progression: megakaryoblast, promegakaryocyte, mature megakaryocyte, platelets

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Neutrophils

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= primary white blood cell type, constitute a major part of the innate immune system
Functions:
- motility: selectively localize, adhere, and cross endothelial lining in response to activating substances released in infection. Disorders: lazy leukocyte syndrome, rheumatoid arthritis, diabetes, alcohol
- phagocytosis: recognize and engulf bacteria/fungi labeled w/ complement/immunoglobulin. Disorders: decreased opsonizing antibodies (B-cell malignancies), corticosteroids, alcohol
- microbial killing: fuse lysosomes with phagocytic vesicles and destroy microbs w/ ROS. Disorders: chronic granulomatous disease, Chediak Higashi syndrome, myelodysplastic syndrome
- Also: degranulation (release of granules), secretion of neutrophil extracellular trap (traps microbes in smaller area, allows degranulation to be more effective), predominant cells of pus (responsible for whitish appearance)
Morphology:
- contain staining (primary/non-specific) and non-staining (secondary/specific) granules. Have FC-receptors and complement surface receptors that allow them to better phagocytose bacteria (coated w/ immunoglobulins or complement)
- premature bands, characterized by curved nucleus, undergo granulopoiesis to become mature segs, characterized by segmented nucleus and filament connecting lobules.

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Monocytes

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Functions:
1. phagocytose bacteria and fungi (though not as efficiently as neutrophils)
2. process antigens for immunocytes
3. become tissue macrophages when attached to tissues
Morphology:
- irregular shaped/round nucleus with chromatin creases (cerebriform folding) and red-purple reticular chromatin that is more open and doesn’t tend to segment
- gray, basophilic cytoplasm with fine red granules

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Eosinophils

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Function:
- very inefficient phagocytes
- release granules (histamine, etc) in response to inflammatory signals (IL-5 produced by T-cells in response to parasitic antigens or allergens—can be dysregulated by increased release in neoplasm: T-cell lymphoma)
- important for innate immunity, allergic disorders
Morphology:
- usually bilobular nucleus w/ large, orange staining granules

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Basophils

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Function:
- release histamine and vasoactive mediators
- responsible for hypersensitivity reactions (anaphylaxis)
Morphology:
- large, purple granules

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Causes of aplastic marrow

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1. Iatrogenic: marrow damaging chemo/radiation (most common)
2. clonal hemopathies that effect function (AML, MDS)
3. Invasive malignancies (leukemia, myeloma)
4. Aplastic anemia: rare disorder of loss of hematopoiesis. Mostly autoimmune (T-cell mediated), treatment w/ allogenic stem cell transplant (<20yo) or immunosuppression

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Hemoglobin switching

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In the first 6mo of life the hemoglobin content in the blood switch from fetal prominent to adult.
- patients with sickle cell or β thalassemias therefore do not present until 6-12mo of age (α chain is found in utero so defects present immediately). Persistence of fetal Hb could be a way to treat these diseases
Hb F (2α, 2γ): greater affinity or O2 allowing it to steal it from maternal blood

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Aspergillus

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= infectious mold
Epi: incidence 15/100k, most common fungal infection post-transplant, typically found in environement (wet hay, wood)
Species: A. fumigatus, A. flavus, A. niger, A. terrae
Infection:
- colonization: occurs in airways of patients w/o good mucous clearance (CF, cilial dysfunction/immotility), aspergilloma forms in pre-existing cavity (COPD, sarcoid)
- invasion (hematogenous): pulmonary, tracheobronchitis, sinusitis (likes to grow in brain), cutaneous, disseminated
Imaging:
- aspergilloma: halo-nodular infiltrate w/ surrounding ground glass. Progresses to air-cresent sign
Tx: voriconazole +/- echinocandin (secondary: amphotericin B, posaconazole, echinocandins)

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Murcomycosis (Zygomycosis)

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= invasive mold
Epi: 1.7/100K, high mortality (50-60%), rapidly progressing disease
Risks: neutropenia, immunocompromise (stem cell or solid organ transplant, RA, cancer, DKA
Pathogenesis: spores inhaled and deposited on mucosa→ germination and tissue invasion. Stimulates angioinvasion causing necrosis
Clinical manifestations:
- rhinocerebral: nasal congestion, pain behind eye, proptosis, altered mental status
- pulm: dyspnea, fever, non-productive cough, pleuritic chest pain
Dx: culture grows rapidly, few hyphae
Imaging: opacification of sinuses, opacification and edema behind eyes, large dense lung infiltrates
Tx: amphotericin B, posaconazole (alternate: add echinocandin)

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Acute Lymphoid Leukemia (ALL)

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= uncontrolled production of precursor B- cell lymphoblasts in the bone marrow replacing normal cells
Epi: most common malignancy of childhood, ¾ of all leukemias, 2.8/100k/year, peak 2-3y, M>F,
Pathogenesis: combination of autoimmune state (lymphoblast hypersensitivity) and lack of environmental exposure to pathogens in infancy then exposure later (limited immune challenge)
Risks:
- genetic: Down’s, Bloom’s breakage syndrome, Nijmegen breakage syndrome, immunodeficiency (ataxia telangiectasia)
- environmental: ionizing radiation, topoisomerase II inhibitors, identical twin of ALL patient (due to malignant transfer of cells through placenta), “late” common infections
Presentation: anemia (malaise, heart failure—edema, orthopnea), thrombocytopenia (hemorrhage, petechiae, bruising), leukopenia (infection/fever), systemic involvement (fever, weight loss, malaise, decreased activity), extramedullary (lymphadenopathy, hepatosplenomegaly, bone/joint pain, CNS-chloromas, renal failure, masses—skin, testicular)
Dx: CBC (↓Hb, ↓platelets, ↓/↑leukocytes) peripheral smear (blasts not usually present), bone marrow morphology (large, immature cells w/ large nucleus, scant cytoplasm, some nucleoli) & flow cytometry
Stratification (high risk indicators at presentation): age (<1yo, >10y), WBC (>50K), location (CNS positive), immunophenotype (T-cell, biphenotypic, multiple lineages), cytogenetics (MLL, Ph’+, hypodiploid), response to initial therapy (at 4 weeks >1% of marrow)
Complications: anterior mediastinal mass (obstructing airway), tumor lysis syndrome (renal failure), hyperleukocytosis (sluding →stroke, ARDS), sepsis
Tx: induction, consolidation, delayed intensification, CNS prophylaxis (lumbar puncture), tx of extramedullary disease, maintenance 1.5-2.5y

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= Reed-sternberg cell. Characteristic of Hodgkin’s Lymphoma
- transformed post-germinal B cell: release cytokines affecting the immune system and causing severe inflammation, fevers, and derangement of immune cell maturation
- often contains Epstein-Barr viral RNA transcripts
- Difficult to find: rare in lymph nodes (need excisional rather than needle biopsy), non-unique cell surface markers (flow cytometry negative)

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Diffuse Large B-cell Lymphoma (DLBCL)

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= most common type of non-hodgkin lymphoma, intermediate grade
Presentation: B symptoms (fever, night sweats, fatigue, weight loss), bone pain, lymphadenopathy
Dx: CBC (↑WBC, ↓LDH), node biopsy, immunohistochemistry. Stage w/ Ann Arbor
Prognosis: international prognostic index
Tx: 6x R-CHOP (rituximab, cyclophosphamide, hydroxyl doxirubicin, Oncovin (vincristine), prednisone). Cure rate >80%

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Follicular lymphoma

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= 2nd most common NHL, low grade
- median age 60, more common in Caucasians
- t(14:18) in 85% of cases (IgH-BcL2): allows for evasion of apoptosis. Not sufficient for disease, requires other mutaitons
- 3%/y transform to aggressive lymphoma (DLBCL), poor prognosis. Cytoxic chemo may accelerate
Tx:
- asymptomatic: no survival advantage (~10% response rate to observation). 70% 5y survival w/o treatment)
- symptomatic (usually mass effect from nodes): rituximab (induction + maintenance), median survival 20 years

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Burkitt’s Lymphoma

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= uncommon high-grade B-cell lymphoma, possibly fasted growing malignancy
Forms:
- endemic in Africa (EBV related, jaw swelling), peak 6-8y, from memory B cells
- non-endemic (systemic disease/abdomen, HIV related), from germinal center B cells
Characteristics:
- hallmark t(8:14): IgH-C-Myc, immunoglobulin heavy chain + C-Myc oncogene (transcription factor causing massive over-proliferation if over expressed)
- proliferation index ~100% (DLBCL ~50-60%), doubling time may be up to 24hrs
- Epi: children 11y, adults 30y, M>F, 1% of NHL (exl. HIV)
Marrow: hyper cellular, large, monomorphic cells w. vacuoles (“starry-night”)
Tx: rituximab intensive regimens, >80% cure rate (50-60% of endemic if treated)

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Myelodysplastic syndromes (MDS)

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= marrow dysfunction causing insufficient production of normal myeloid cells. 10-15% progress to AML
Risks: ↑age, prior mutagenic chemotherapy
Presentation (subacute): general poor feeling, also anemia, bleeding, infections, AML
Dx:
- labs: anemia, neutropenia, thrombocytopenia
- marrow: hypocellularity, mild dyserythropoiesis, hypogranular granulocytes w/ Pelger Huet nucleus, +/- ringed sideroblasts, myeloblasts w/ abberant markers, hypo-lobulated megakaryocytes

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Chronic lymphocytic leukemia (CLL)

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= B-cell leukemia (more advanced stage of small lymphocytic lymphoma)
Epi: 3/100k/y, most common leukemia of adults (western world, long survival), avg 72y, M>F
Pathophys: B cells are dysfunctional resulting in hyopgammaglobulinemia and may produce autoantibodies causing AIHA & ITP (Evan’s syndrome), also may acquire Richter’s transformation and become large cell lymphoma
Presentation: often Asx, fatigue, weight loss, anorexia, lymphadenopathy, hepatosplenomegaly, infection
Dx: variable WBC, anemia, thrombocytopenia, smudge cells & Evan’s syndrome on smear, CD5 on cytometry (normally T-cell antigen)
Staging: (clinical, but CD38+, ZAP-70 expression, poor response to therapy, -11q, -17p, also increase risk)
- Low: Rai 0 (lymphocytosis only), median survival 14y
- Intermediate: Rai I (lymphadenopathy), Rai II (spleno +/- hepatomegaly), median survival 7y
- high: Rai III (anemia), Rai IV (thrombocytopenia), median survival 4y
Tx:
- indications (5% do not progress): Rai III/IV, lymphocyte count doubling <1y, B symptoms, high risk molecular markers.
- Rx: fludarabine +/- cyclophosphamide & rituxan. If old/comorbidities chlorambucil +/- prednisone

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Plasma cell myeloma (multiple myeloma)

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= plasma cell neoplasm which secretes monoclonal Ig or Ig fragments.
Epi: 4.3/100k/y, median 66y, AA>Caucasians
Pathophys:
- production of IL6 causes bone resorption and lytic lesions, osteopenia, factures, bone pain and hypercalcemia
- decreased production of normal Ig’s increases infection, esp. encapsulated bacteria (pneumococcus, H. influenza)
- malignant replacement of marrow results in reduced erythropoiesis and anemia
- monoclonal hypergammaglobulinemia results in Bence Jones proteinuria (free light chains) and renal failure, hyperviscosity, cryoglobulins, coagulopathy. Light chains may fold and lead to amyloid deposition
- high M proteins (monoclonal Ig) causes high plasma protein and RBC rouleaux
Dx: Bence Jones proteins (serum/urine), clonal marrow proliferation, 1+ CRAB: hyperCalcemia, Renal insuffiency, Anemia, lytic Bone lesions; monoclonal protein spike on electrophoresis
Staging: β2 microglobin (↑ = ↑disease burden), -13q14 (bad), heavy chain gene locus translocation (bad)
Tx: autologous transplant, Imids (thalidomide, pomalidomide, lenalidomide), proteasome inhibitors (bortezomib). These improve survival and remission rates, generally not cureable

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Sideroblastic Anemia

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= microcytic hypoproliferative anemias with “ring” sideroblasts in the marrow (nucleated RBC w/ iron granules in cytoplasm)
Pathogenesis: impaired heme synthesis leading to Fe accumulation in the mitochondria of red cell precursors
Types:
- primary sideroblastic anemia: X-linked responsive to pyridoxine
- autosomal: unresponsive to pyridoxine
- acquired: unresponsive to pyridoxine, caused by: drugs (isoniazid, pyrazinamide, chloramphenicol), alcohol, lead poisoning, chronic inflammation, pre/leukemic state (AML)
Lab: ↓retics, variable MCV, ↑Fe, normal transferring, ↑transferring sat.
Smears: dimorphic pattern of normal RBCs and severely hypochromatic microcytes. Basophilic stippilings may be present. On marrow biopsy numerous pathognomonic ring sideroblasts and erythroid hyperplasia
Tx: high dose pyridoxine or folic acid, removal of causal agent

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Amplification of the clotting cascade

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= feed forward loop allowing a few molecules to activate a large number of processes (1 VII molecule activates 10,000 thrombin molecules) and overcome basal thrombosis inhibition
- occurs when endothelial lining becomes exposed (activating platelets) and tissue factor (on endothelial cells, monocytes, and extravascular cells) is expressed (activating coag cascade).
- Primary hemostasis: platelets are activated by binding GP1b receptor on vWF forming platelet plug (white clot, predominantly arterial system)
- secondary hemostasis: generation of thrombin (factor IIa) through intrinsic/extrinsic activation, causing conversion of fibrinogen into fibrin monomer which traps RBCs (“red clot,” predominantly venous)

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Control of coagulation

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Localization of tissue factors:
- TF expressed on specific cells rather than platelets, only exposed after damage
- activated coagulation factors bound to cell surfaces are relatively protected from degradation by plasma protease inhibitors
Compartmentalization to epithelium
- sub-epithelial exposure required for platelet activation
- tissue factor plasma inactivator inhibits VIIa and Xa
- Proteins C, S inactivate factors VIIIa and Va and bind thrombin (w/ thrombomodulin)
- heparin and antithrombin inhibit factors Xa, IXa, IIa. Prevent thrombin diffusion from site of injury
Fibrinolysis:
- thrombin promotes tissue plasminogen activator leading to fibrinolysis and clot destruction

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Secondary hemostasis

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Phases:
Initiation: vascular damage/inflammation cause exposure of tissue factor on extravascular cells (and monocytes/endothelial cells) which complexes with VIIa to generate a small amount of thrombin—extrinsic pathway (alternatively the intrinsic pathway is independently activated by endothelial damage)
Amplification:
- thrombin production enhances platelet adhesion and fully activates platelets: platelets then spread out and provides surface for coagulation factor complexes to act)
- thrombin activates V, VIII, XI initiating the intrinsic pathway
Propagation:
- Xase complex (VIIIa, IXa and X) and prothrombinase complex (Xa,Va,II) assemble on the platelet surface and initiate large scale thrombin generation and production of fibrin
- thrombin activates thrombin activatable fibrinolysis inhibitor (TAFI) preventing breakdown of fibrin (partially degrades fibrin to limit plasminogen binding). Plasminogen activator inhibitor and α2-antiplasmin also inhibit plasmin generation/action to prevent excess fibrinolysis

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Labs evaluating secondary hemostasis

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Common: (do not necessarily predict bleeding if abnormal, standards vary by lab)
- protime (PT, 11-15sm, factor VII, common): tissue factor (extrinsic) defects, citrated plasma assay w/ thromboplastin + Ca
- activated partial thromboplastin time (aPTT, 25-25s, factors XII, XI, IX, VIII, common): contact factor/thromboplastin (intrinsic) defects, activated means contact surface (particulate silica), partial means after organic extraction procedure. Citrated plasma + pthromboplastin + Ca + silica
- thombin time (TT): measures conversion of fibrinogen to fibrin and fibrin cross linking (tests: normal fibrinogen amount, ability to generate fibrin monomer and polymer, effect of antithrombin and heparin)
- Mixing study: combine abnormal w/ normal plasma and see if clotting problem resolved: positive correction indicates factor deficiency, negative/partial/reversal after incubation indicates inhibitor (antibody)
Uncommon:
- Fibrinogen:
- Fibrinogen/Fibrin degradation products:
- Individual factor levels

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Acquired Hemophilia

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= autoimmune disease against coagulation factors (most commonly VIII, others RARE)
Epi: 1.4/mill (0.045/mil <16y, 14.7/mil >85), 6-20% mortality (esp elderly w/ underlying disease), a/w autoimmune conditions, pregnancy, malignancy
Clinical picture: severe bleeding in patient w/o disorder: bruising, mucosal bleeding, deep muscle bleeding, severe GI bleeds
Dx: prolonged aPTT, mixing study w/ time/temp dependent inhibition and reversal w/ prolonged incubation, Bethesda assay (compares VIII activity to normal, known deficient) higher = more antibody
Tx:
- control bleeding: low titer (give VIII, human or porcine), high titer (bypass agent, FEIBA or VIIa)
- eradicate inhibitor: many regimens (steroids +/- Cytoxan, immune tolerance ,IV Ig, rituximab, cyclosporin, no treatment). Usually can eradicate if they survive the initial presentation

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Hemophilia

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= clotting factor deficiency (congenital, acquired) (problem w/ secondary hemostasis)
Presentations: (bleeding usually delayed, deep, joint (congenital)/muscle (acquired)), menorrhagia, hemorrhagic bullae, bleeding into CNS, spontaneous bleeding into joints (fingers, wrists, feet, spine), hemarthrosis (bleeding into joint), GI bleeds (hemotypsis), microscopic hematuria, splenomegaly
Types:
- A: x-linked recessive, VIII deficient, 80% (1/10K male births)
- B: x-linked recessive, IX deficient, 20% (1/50K male births)
- C: AR (some heterozygous penetrance), XI deficient
Severity: severe (<1% active factor), moderate (1-5%), mild (5-40%)
Tx: recombinant or attenuated factor replacement. Risks: auto-antibody development (former), infectious disease (latter). If refractory recombinant VII can partially overcome

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Lupus Anticoagulant

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= antibodies that inhibit phospholipid dependent coagulation tests in vitro and are neutralized by excess phospholipids (most people do not have lupus and it’s not an anticoagulant)
Prevents coagulation in the tube but in vivo binding phospholipid causes membrane damage and clotting
Presentation: thrombosis
Work up: VIII assays >10%, PTT w/ dilution increased, will not correct on mixing study, PT and DRVVT may be

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Warfarin

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= anticoagulant that inhibits Vit K reductase, preventing Vit K dependent conversion of precursor clotting factors X, IX, VII, II, proteins S, C (diSCo 1972)
- When initiating therapy there is a brief period of increased hypercoagulability b/c protein C is depleted before the clotting factors

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Vitamin K deficiency

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Causes:
- infancy (gut not fully colonized): can result in hemorrhagic disease in newborns (intercerebral, GI, umbilical, ENT bleeds), early (1d, anti-convul, anti-TB), classic (1-7d, idiopathic, maternal drugs), late (2-24wks, idiopathic, malabsorption, liver dz, breast feeding)
- malabsorption
- hyperemesis gravidarum
- fasting (>3-7d)
- alcoholism
- drugs: Warfarin, maternal anticonvulsants, antibiotics (loss of gut precursors), Vitamin E megadose, salicylates
Treatment:
- Asx: oral or IM vit K replacement
- Bleeding: FFP, recombinant VIIa or Vit K +/- prothrombin complex concentrates

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Factor synthesis

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- except for vWF all (+protein C,S, thrombopoietin) are synthesized in the liver (PPT is a good LFT)
- liver failure can cause coagulation problems (deficiency), or if chronic splenomegaly can trap platelets causing severe bleeding

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Anticoagulants

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Heparin: binds and inhibits antithrombin
Lepirudin, agatroban, bevilrudin, dabigatran: direct thrombin inhibitors, don’t have to measure levels
Rivaroxaban: Xa inhibitor (no antidote)
Warfarin: vitamin K dependent inhibitor (X, IX, VII, II, S, C)

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Thrombocytopenia

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= low platelet count resulting in problems with primary hemostasis
Presentations: (bleeding usually immediate, superficial, mucosal) petechiae (lower legs, mouth), mucosal bleeding (gums), contusions (bruises), ecchymosis (bruise >1cm), purpura (non-blancing patches), menorrhagia, prolonged wound bleeding, epistaxis, GI bleeds (hemotypsis), microscopic hematuria, splenomegaly
Ddx: decreased platelet production, increased platelet destruction, platelet sequestration, dilutional thrombocytopenia (after massive hemorrhage), pseudo-thrombocytopenia (artifactual platelet clumping)
Dx: platelet count (<150K/mcL), Hb/WBC, smear/marrow. Platelet function analyzer if normal count but signs (screen for dysfunctional platelets)

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Platelet production/destruction syndromes causing thrombocytopenia

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Reduced production:
- Congenital: large platelets (MYH-9 disorders, Alport syndrome, Bernard Soulier), normal size (fanconi, congenital amegakaryocyte thrombocytopenia), small platelets (Wiscott Aldrich syndrome)
- Acquired: primary dz of the marrow (marrow failure/aplastic anemia/leukemia, myelo/lymphoproliferative dz, MDS), secondary (meds, chemo/rad, alcohol, vitamin deficiency (B12, copper, folate), marrow infiltration, viral, liver dz (↓thrombopoietin))
Increased destruction:
- Immune: primary (ITP), secondary (heparin induced T, GP1b antagonists, meds, CT dz, lymphoproliferative dz, infection, neonatal alloimmune thrombocytopenia, post-transfusion purpura)
- Non-immune: DIC, TTP, hemolytic uremic syndrome, vasculitis
Disruption of laminar flow, drug-induced platelet consumption (drug induces Ab, platelet/drug removed)

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Immune thrombocytopenia (ITP)

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= heterogeneous disorder of primary immune platelet destruction
Characterized by: isolated thrombocytopenia (platelets < 100K), no obvious underlying cause, +/- bleeding, 20% secondary (due to drugs, infection, autoimmune disease)
Epi: 1.5-4/100k/y, 20-50y, F>M, risk of major bleeds ↑w/ age
Pathogenesis: anti-platelet Abs causing destruction by macrophages, inhibition of megakaryocyte maturation/proliferation and release from marrow
Phases: new dx (<3mo, mostly children), persistent (3-12mo), chronic (>1y, most adults)
Dx: marrow (↑megakaryocytes), smear (↓platelets, may be large), other studies: anti-phospholipid Ab, anti-TSH Ab (other anti-thyroid Abs), ANA, pregnancy test, parvovirus or CMV PCR, platelet GP specific Abs
Tx: (stop bleeding, ↑platelets and maintain at >30K, avoid toxicities/complications)
- first line: steroids (dexamethasone), IV Ig, Anti-D (RhoGam)
- second line: splenectomy, danazol, immune suppression (azathioprine, cyclosporine, dapsone, mycophenolate mofetil), chemo (cyclophosphamide, vincristine), rituximab, TPO receptor agonists

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Heparin-induced thrombocytopenia

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= secondary immune platelet destruction
Pathogenesis: heparin therapy induces anti-heparin antibodies which then removes platelets after heparin binds to them
Epi: 1% of patients on heparin (higher risk in unfractionated vs. LMWH)
Prediction algorithm (4 T’s: thrombocytopenia, Timing of platelet fall, Thrombosis or other sequelae, other causes for Thrombocytopenia). Low <3 (<1.6% have HIT positive assay), Intermediate 4-5 (7.9-28.6%), high 6-8 (21-100%)
Dx: HIT assay,
Tx: immediate discontinuation of heparin w/ appropriate anticoag substitution

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Thrombotic Thrombocytopenic Purpura (TTP)

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Pentad of symptoms: hemolytic anemia (schistocytes on smear), thrombocytopenia, renal insufficiency, neurologic changes, fever
Pathogenesis (congenital & acquired): deficient ADAMTS13 (vWF cleaving protease) so large vWF multimers activate platelets causing systemic thrombosis
Types: acquired (Ab inhibitor of ADAMTS13), congenital (deficiency of ADAMTS13, discovered in 1998)
Tx: plasma exchange (removes Ab, replaces ADAMTS13), inhibitors of vWF (in trials), recombinant ADAMTS13
Prognosis: historically death w/in 12hrs of dx

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Hemolytic Uremic syndrome

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= formation of clots in the glomerulus
- #1 cause of acute renal failure of children
Classic triad: intravascular hemolytic anemia, thrombocytopenia, renal failure
Acquired due to infection (90%)
- E. Coli 0157:H7; shiga toxin damages endothelium, causes large release of vWF multimers and recruitment to glomerulus
- prodrone of bloody diarrhea
Genetic (atypical HUS) (10%)
- mutations in complement pathway (factor H) causing compolement to be activated on endothelial cells (destruction, vWF release)
- damage cause thrombosis in the glomerulus
Tx:
- acquired: supportive care (transfusion, dialysis)
- atypical: poor prognosis w/ renal failure (a transplant would also be affected, loss of graft in 1 year). New treatments: eculizumab (ant-C5 monoclonal Ab)

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Presentation of inherited hemolytic anemia

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- neonatal jaundice: increase bilirubin from RBC destruction
- personal/family hx of premature gall stones (increase Hb destruction causing ↑bile salts)
- personal/family hx of anemia, splenectomy
- specific diagnosis of hemolytic anemia
- chronic or recurrent symptoms: vague aches, pain, ulcers

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Pathophysiology of inherited hemolytic anemias

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Spherocytosis: RBC’s w/o central pallor, AD, spectrum of severity
- mutations in ankyrin: protein anchoring cytoskeleton (of spectrin proteins) to cell membrane
- “vertical defect” resulting from abnormalities in binding, structure, or quantity of proteins
- loss of membrane stability (not secured by matrix) results in loss of membrane fragments with age → ↓surface/volume ratio → sphere shape, decreased membrane lipids, altered membrane phosphorylation, ↑osmotic fragility → undergo lysis in hypotonic sln, trapping in the spleen
Elliptocytosis: >20% elongated RBCs, AD, spectrum of severity
- spectrin mutations, horizontal defects in cytoskeleton
Pyropoikilocytosis: increased sensitivity to heat (severe form of elliptocytosis)
- deletions in spectrin molecules (“horizontal defects”) cause RBC fragmentation when exposed to heat

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G6PD deficiency

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= X-linked recessive disorder causing episodic hemolytic anemia
Epi: 10-15% of mediterraneans, 7% AA’s (possible protective effect against malaria)
- G6PD generates NADPH: used as a reducing equivalent in production of reduced glutathione (important for detoxification of ROS via glutathione peroxidase)
- G6PD is part of anaerobic glycolysis, required for anaerobic ATP generation
Pathogenesis: w/o oxidants accumulate causing injury. Typically don’t get clinical presentation until stressed (infection, drugs) by increasing RBC destruction and overwhelming ability to deal w/ oxidative stress. Oxidants denature Hb sulfhydryl groups, causing precipitation as Heinz bodies
Instigating exposures: infection (viral hepatitis, pneumonia, typhoid fever), drugs (anti-malarials, sulfonamides, nitrofurantoins), fava beans
Dx: on smear: Heinz bodies (precipitated, denatured Hb), bite cells (macrophage removal of Heinz bodies, may revert to spherocytes)

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Intra vs Extravascular hemolysis

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Both: hemolytic anemia ( ↓Hb, ↑retic), usually normocytic
Intravascular: (can cause hemoglobinuria, leading to Fe deficiency)
- hemolysis w/in vessels
- ↑Hb in plasma and urine
- Hemosiderinuria (renal tubules convert iron to hemosiderin)
- ↓haptoglobin (to reclaim serum Hb)
Extravascular:
- RBC phagocytosis by macrophages in spleen or liver
- ↑unconjugated bilirubin (UCV) → jaundice, bilirubinate gallstones (black)
- ↑LDH

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Primary hemostasis

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Platelet tethering/adhesion
- endothelial injury exposes subendothelium contain vWF and collagen. Platelets tether to vWF by GP1B-1X, then adheres to surface w/ integrin αIIbβ3 and is activated
Platelet activation
- Activated platelets release stored dense, alpha gransules (ADP, serotonin, platelet-activating factor (PAF), vWF, platelet factor 4, thromboxane A2) causing mass activation/deposition of platelets.
- platelet aggregation occurs in 2 waves: 1st from exogenous agonists (ADP/collagen), second from endogenous release of granules
Platelet stabilization:
- granule contents activate Gq-linked protein receptor cascade → ↑ platelet [Ca]→ phospholipase A2 activation (via PKC) → conformational change in integrin membrane glycoprotein IIb/IIIa exposing fibrinogen binding site→ ↑fibrinogen binding affinity, change to stellate platelet shape, phosphatidylserine flipping to external membrane (pro-coagulant), fibrinogen crosslinking

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Von Willebrand Factor

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= 2050AA glycoprotein involved by in hemostasis
- synthesized by endothelial cells and megakaryocytes, circulates as multimers, has functional binding and cleavage sites for VIII, GP1b, collagen, integrin αIIbβ3, and ADAMTS13
Functions:
- recruitment of platelets to sites of vascular injury: resides in vascular subendothelium bound to collagen, when exposed tethers platelets to damaged vascular wall and eachother
- carrier protein for factor VIII: prolongs VIII T1/2 by protecting proteases (10-12h v. 2h), VIII released from vWF by thrombin action allowing it to get to site of damage more quietly. W/o
Dysfunction/deficiency: leads to bleeding, especially in tissues w/ high blood flow shear in narrow vessels
Normal level variations: stress/exercise (↑endothelial release for impending injury), pregnancy/OCP, age, acute/chronic inflammation, hypothyroidism and type O blood a/w low vWF

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Platelet studies

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Platelet agonists:
- ADP, collagen, thromboxane, thrombin
- Measure aggregation (αIIbβ3)
Other agents:
- ristocetin, botrocetin
- measure agglutination GP1b-IX

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Platelet adhesive receptors

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GP1b-V: interacts with vWF to tether platelets to subendothelium and in itiate activation via inside-out signaling
Integrin αIIbβ3 (Gp11B-IIIa): ADP binding → ↑[Ca] intracellular, triggering conformational change in these surface proteins exposing binding site and allowing fibrinogen binding and platelet cross-linking
PAR (protease activated receptors): bind thrombin, which stabilizes the platelet plug and converts fibrinogen to fibrin.
GVPI: interacts w/ PAR to initiate Ca signaling and other intercellular pathways
Α2β1: collagen receptor

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Disorders of primary hemostasis

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Presentation: petechiae, purpura, ecchymosis, mucosal bleeds (oral, nose, GI, menstrual)
Quantitative disorders: (more common), low number of platelets
Qualitative disorders: adequate platelets (150-400 K/mcL, hemostatic insufficient evident at <30K), inadequate function
Causes:
Acquired:
- meds: COX inhibitors (aspirin, NSAIDS), clopidogrel (Plavix, irreversible inhibits platelet ADP receptor), abciximab (Reopro, chimeric monoclonal Ab to integrin αIIbβ3, mostly w/ stents)
- myeloproliferative disorders: abnormal platelet maturation in the marrow
- systemic illnesses: cardiopulmonary bypass (destruction), uremia/renal dysfunction (accumulated metabolites impair platelet function, corrected w/ dialysis)
Congenital:
- Glanzmann thrombasthenia (absence of αIIbβ3)
- Bernard – Soulier syndrome (absence or dysfunction of GP1B-IX)
- Absence of platelet granules: dense (δ) deficiency (ATP, Ca), alpha (α) deficiency (vWF, fibrinogen)
- dysfunctional granule release

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Glanzmann thrombasthenia

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= congenital absence of αIIbβ3 (qualitative platelet disorder)
- presents as normal platelet count w/ mucocutaneous bleeding
- in vitro: platelets will not aggregate w/ addition of ADP or thromboxane (but will w/ ristocetin—binds vWF to Gp1B)
- Atypical form: preceptor present at low to moderate levels but is dysfunctional: inside-out activation does not occur or there are mutations at the fibrinogen binding site
- Labs show: microcytic anemia, platelet cound of 190K/mcL, large platelet size

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Bernard-Soulier Syndrome

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= congenital absence or dysfunction of GP1b-IX
- causes thrombocytopenia w/ giant platelets (GP1b-IX involved in megakaryocyte maturation)
- platelets will aggregate normally, but do not agglutinate w/ ristocetin

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Congenital absence of platelet granules

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= inherited disorder of primary hemostasis
Dense (δ) granule deficieny
- normally contain ATP and Ca (contribute to inside-out signaling)
- mutations identified in several genes that regulate platelet dense granule and melanosome synthesis
- associated w/ varying degrees of albinism in mice
Alpha (α) granule deficiency
- normally contain vWF and fibrinogen (contribute to platelet aggregation)
- platelets appear gray in Wright’s stain instead of basophilic (“Gray platelet syndrome”)

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von Willebrand Disease

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= most common hereditary coagulation disorder (some acquired) due to quantitative or qualitative deficiency of vWF. Leads to mucosal bleeding, esp in tissues w/ high blood shear force (arterial)
Quantitative:
Type 1: 75-80%
- AD inheritance w/ highly variable penetrance. Not linked to vWF gene, but other genes that modify it
- primarily due to decreased synthesis and plasma secretion of vWF, but occasionally due to increased clearance
- Dx: <100 IU/dL of vWF, <30% vWF activity (if higher, take account FHx, bleeding hx)
Type 3: 1-3%
- AR, a/w vWF gene loci with no detectable vWF produced
- most severe form, causing severe mucosal bleeding, occasionally hemoarthroses (due to low VIII—normally binds vWF)
- Dx: bleeding/family Hx, no vWF detected
Qualitative:
Type 2: 15-20%, 4 subtypes (A, B, M, N)
- due to defect in one of the functions of vWF, will have normal/high circulating vWF levels but structurally abnormal multimers
- Dx: normal/high vWF, variable multimer patterns (depending on subtype), low VIII (if abnormal binding) may be hard to distinguish from hemophilia A), low platelets/vWF from clumping: 2B
Tests:
- global tests of primary hemostasis (modified by stress, exercise, age, pregnancy/OCP, inflammation, hypothyroidism, type O): platelet function assay, platelet aggregation studies
- vWF antigen: measures amount circulating in plasma (can also be directly measured w/ ELIZA)
- Ristocetin cofactor activity: causes GP1B-IX binding to vWF, tests functionality of vWF
- collagen binding assay: tests vWF functionality in binding collagen
- factor VIII activity: measures carrier function of vWF
- vWF multimer analysis: helps distinguish type 2 subtypes by examining multimer populations

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Treatment for disorders of primary hemostasis

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DDAVP (Stimate): for vWD (type 1, some type 2), mild platelet function disroders/uremia
- synthetic vasopressin, intranasal or parenteral
- mimics stress response—induces release of vWF from endothelium. Increases platelet “stickiness”
- can cause hyponatremia (esp. young kids) from ADH action, caution against excess fluid
Anti-fibrinolytics: (aminparoid acid, tranexamic acid) for mild platelet dysfunction
- prevent clot lysis, esp useful in menstruating women
Attenuated VIII products w/ high vWF (Humate P, Wilate): for vWD
- dose based on vWF:Ristocetin assay, 12-14hr T1/2
Activated VII (VIIa, Novoseven): for acquired hemophilia disorders
Platelet transfusion: for quantitative platelet disorders
- risky b/c of allergic reaction, infectious dz transmission, alloimmune reaction (to platelet HLA antigen, platelet receptor GPIIbIIIa—Glanzmann thrombasthenia)
Bone marrow transplantation: last resort

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Disseminated Intravascular Coagulation (DIC)

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= wide spread activation of coagulation (primary/secondary)
- results in fibrinolysis activation (TPA/plasmin), consumption of factors and inhibitors
- multi-system end-organ damage due to microthrombi (present in most patients at autoposy)
Presentation: ↑clotting times, ↓platelets, signs of bleeding (oozing at multiple sites), clinical or subclinical thrombosis
Causes: generally due to release of TF (onbstetrics, trauma), LPS (sepsis), hemolysis, acidosis, turbulence
Common: sepsis (→ARDS), malignancy (adult carcinomas, acute promyelocytic leukemia t(15,17)), trauma (head), burns, obstetric (placental abruption, amniotic embolism, eclampsia, retained fetus)
Rare: vascular (aortic aneurysm, giant hemagioma), toxins (snake venom), transfusion, immunologic (allergic rxn, collagen vascular disease, transplant)
Dx: PT/PTT (not useful), fibrinogen (↓), platelet count (↓, variable), FDP (↑), d-dimers (pos/abn)
Tx (remove inciting event): FFP (if prolonged PT/PPT), cryoprecipitate (keep fibrinogen >100), platelets (keep >50k), fibrinolytics not recommended, heparin not clear