Hematology Survival Guide

Evaluation of Bleeding Disorders

Hemostasis Physiology

Bleeding control involves a coordinated series of processes that work together to form stable clots:

Primary hemostasis involves platelets forming the initial plug through three sequential steps:

1. Adhesion - vWF molecules bridge platelets to exposed subendothelium via GP Ib receptors
2. Activation - Platelets receive signals through thromboxane A2 (TXA2) and ADP release
3. Aggregation - GP IIb/IIIa receptors cross-link platelets together using fibrinogen as the bridge

Secondary hemostasis creates the fibrin scaffold that stabilizes the platelet plug. The coagulation cascade is organized into three interconnected pathways:

• Extrinsic pathway - Tissue factor + Factor VII activate Factor X (fastest, 5 seconds)
• Common pathway - Factors I, II, V, and X complete clot formation
• Intrinsic pathway - Factors XII, XI, IX, and VIII activate Factor X (slower, 1-2 minutes)

Factor X serves as the critical convergence point where extrinsic and intrinsic pathways merge. The final reaction produces fibrin monomers that polymerize into cross-linked clots. Plasmin later breaks down fibrin into D-dimer fragments, enabling fibrinolysis.

Antiplatelet and Anticoagulant Agents

Agent	Mechanism	Pathway Affected	Duration
Aspirin	Irreversible TXA2 synthesis inhibition	Primary hemostasis	7-10 days
Clopidogrel	ADP receptor antagonism	Primary hemostasis	5-7 days
Dipyridamole	Phosphodiesterase inhibition	Primary hemostasis	Hours
Warfarin	Vitamin K antagonism (Factors II, VII, IX, X, Proteins C & S)	Extrinsic + Common	3-5 days
Fondaparinux	Indirect Factor Xa inhibition via ATIII	Common	2-4 days
Apixaban	Direct Factor Xa inhibition	Common	12-24 hours
Rivaroxaban	Direct Factor Xa inhibition	Common	24 hours
Dabigatran	Direct thrombin (IIa) inhibition	Common	24-36 hours
Lepirudin	Direct thrombin (IIa) inhibition	Common	Hours
Argatroban	Direct thrombin (IIa) inhibition	Common	Hours

Clinical Evaluation Algorithm

The pattern of abnormal laboratory results guides diagnosis of hemostatic defects:

Mixing Studies

Mixing studies help differentiate between factor deficiencies and inhibitors:

Mixing Study Interpretation

When a patient's prolonged PT or PTT is investigated:

• Corrects after mixing with normal plasma → Factor deficiency (supply missing factor)
• Remains prolonged after mixing → Inhibitor present (antibody against factor VIII, IX, XI, or XII)

This distinction guides treatment. Factor deficiencies may benefit from replacement therapy, while inhibitors require immune suppression or bypass agents.

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Anticoagulant Reversal

Reversal Strategies

Anticoagulant	Acute Reversal Agent(s)	Dosing	Notes
Warfarin	Vitamin K IV	2.5-5 mg (stable INR 4.5-10); 10 mg (INR >10)	Onset 12-24h; hold warfarin first
	KCentra (Prothrombin Complex Concentrate)	1,500-2,000 units IV	Immediate effect; preferred for active bleeding
	FFP	2-4 units IV	Last resort if KCentra unavailable
Apixaban/Rivaroxaban	Andexanet Alfa	Weight/dose-based bolus + infusion	Specific reversal; FDA approved
	KCentra	50 units/kg IV	Reasonable alternative
	Tranexamic acid	1-1.5 g PO q8h	Consider as adjunct
Dabigatran	Idarucizumab	2-5 mg IV q10 minutes × 2 doses	Specific monoclonal; FDA approved
	Emergent hemodialysis	N/A	Dabigatran is dialyzable
	Tranexamic acid	1-1.5 g PO q8h	Consider as adjunct
Unfractionated Heparin	Protamine Sulfate	1 mg per 100 units heparin	Dose adjusted by time since last dose
		Given as slow IV infusion	Monitor PTT 5 minutes after
Low-Molecular-Weight Heparin	Protamine Sulfate	1 mg per 100 units LMWH	Partial neutralization only (~60%)
		Give slowly IV	Repeat dose q2-4h if needed
Aspirin	Platelet Transfusion	1 unit (or pool of 6)	Temporary effect
		Consider for active bleeding only	Effective for 3-7 days post-aspirin
Clopidogrel	Platelet Transfusion	1 unit (or pool of 6)	Similar to aspirin
	DDAVP	0.3 mcg/kg IV	For platelet dysfunction/uremia

Clinical INR Management (Warfarin)

INR-Based Warfarin Management

INR 4.5-10 without bleeding:

• Hold warfarin doses and recheck INR in 2-4 days
• No immediate reversal needed

INR >10 without bleeding:

• Hold warfarin
• Give vitamin K 2.5-5 mg orally (slower, safer) or IV (faster but higher reversal risk if over-correcting)
• Recheck INR in 12-24 hours
• Consider KCentra if urgent surgery planned

Active bleeding at any INR:

• STAT: Vitamin K 10 mg IV slow infusion + KCentra 1,500-2,000 units IV
• Recheck INR 15-30 minutes after
• May repeat KCentra if still elevated

Perioperative Anticoagulation Holding Times

Anticoagulant	Hold Before Surgery	Resume After Surgery
Warfarin	5 days (INR <1.5)	Evening of surgery or day 1
Apixaban	2-3 days	24 hours if low bleeding risk; 48h if high
Rivaroxaban	2-3 days	24 hours if low bleeding risk; 48h if high
Dabigatran	2-5 days	24 hours if low bleeding risk; 48h if high
Aspirin	5-7 days	Resume per procedure protocol
Clopidogrel	5-7 days	Resume per procedure protocol
Unfractionated Heparin	Stop 4-6 hours preop	Resume within 24 hours postop
LMWH	Last dose 24 hours preop	Resume 24-48 hours postop

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Leukocytosis

Normal WBC Differential

Cell Type	Normal Range	Associated Conditions
Neutrophils	40-60% (2.0-7.5 K/μL)	Infection, inflammation, stress response, malignancy, medications (corticosteroids), tobacco use, splenectomy, leukemias
Lymphocytes	20-40% (1.0-4.5 K/μL)	Viral infections, pertussis, leukemias, hypersensitivity reactions, chronic infections (TB, brucellosis)
Monocytes	2-8% (0.1-0.8 K/μL)	Autoimmune diseases, chronic infections (tuberculosis, fungi), splenectomy, monocytic leukemias
Eosinophils	1-4% (0-0.4 K/μL)	Allergic conditions, parasitic infections, eosinophilic esophagitis, malignancies (Hodgkin lymphoma), drug reactions, eosinophilic syndromes
Basophils	0.5-1% (0-0.1 K/μL)	Allergic reactions, myeloproliferative neoplasms, leukemias

Left Shift and Immature Cells

A left shift describes the appearance of immature neutrophils (bands, metamyelocytes, myelocytes) in the peripheral blood. This indicates:

• Accelerated bone marrow release in response to infection or severe inflammation
• Typically accompanies moderate to severe leukocytosis
• Suggests acute bacterial infection, sepsis, or acute leukemia

When to Suspect Leukemia

If the differential reveals blast cells (immature myeloid or lymphoid precursors):

• Contact hematology/oncology immediately
• Do not delay bone marrow biopsy
• Flow cytometry should be obtained for definitive classification
• Avoid unnecessary transfusions (may precipitate leukostasis)

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Anemia

Definition and Clinical Features

Anemia is defined as hemoglobin concentration below 12 g/dL in women or 14 g/dL in men. Clinical severity depends on acuity of onset and compensatory capacity.

Common presenting symptoms:

• Fatigue and weakness
• Dyspnea on exertion (or at rest if severe)
• Chest pain or angina (especially in CAD patients)
• Pallor of conjunctivae, palms, and nail beds
• Tachycardia and tachypnea
• Orthostatic hypotension
• Jaundice (suggests hemolysis)
• Splenomegaly (hemolysis, leukemia, cirrhosis)

Initial Diagnostic Approach

The workup of anemia follows a systematic algorithm:

1. Complete blood count with differential - platelet count, WBC, hemoglobin, hematocrit
2. RBC indices and reticulocyte count - Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), Reticulocyte Index
3. Peripheral blood smear - RBC morphology, white cell abnormalities, platelets
4. Iron studies - serum iron, total iron-binding capacity (TIBC), ferritin, transferrin saturation
5. Hemolysis markers if indicated - LDH, haptoglobin, indirect bilirubin, direct antiglobulin test (Coombs)
6. Consider additional testing - B12, folate, TSH, renal function, liver function

Understanding RBC Parameters

Parameter	Meaning	Clinical Correlation
Hemoglobin (Hgb)	Total hemoglobin concentration in whole blood (g/dL)	Primary measure of oxygen-carrying capacity
Hematocrit (Hct)	Fraction of blood volume occupied by intact RBCs (%)	Roughly equals Hgb × 3
MCV	Average RBC volume (fL)	Classifies anemia (micro/normo/macrocytic)
MCH	Average hemoglobin content per RBC (pg)	Low = hypochromic
MCHC	Average hemoglobin concentration in RBCs (%)	High = spherocytes; low = hypochromia
RDW	Distribution width reflecting RBC size variation (%)	High = anisocytosis; broad size variation

Quick RBC Math

• RBC count × 3 ≈ Hemoglobin
• Hemoglobin × 3 ≈ Hematocrit

Use these to quickly verify lab values for internal consistency.

Urgent Clinical Scenarios

Urgent Hematology Situations

• Acute hemorrhage - massive transfusion protocol activation, ICU monitoring
• Microangiopathic hemolytic anemia (MAHA) - disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura
• Sickle cell crisis - vaso-occlusive crisis, acute chest syndrome, splenic sequestration
• Severe leukemias - blast crisis, severe cytopenia, risk of leukostasis
• Aplastic anemia - pancytopenia with infection risk, hemorrhage risk

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Microcytic Anemia (MCV <80)

Iron Deficiency Anemia

Iron deficiency represents the most common cause of microcytic anemia worldwide. Progressive depletion of iron stores impairs hemoglobin synthesis.

Laboratory features:

• Low serum iron, elevated TIBC, low ferritin, low transferrin saturation
• Peripheral smear shows hypochromic microcytic RBCs with possible target cells
• RDW typically elevated (high variation in RBC size)

Clinical signs of chronic iron deficiency:

• Angular cheilosis (cracks at mouth corners)
• Pica (craving non-food items)
• Koilonychia (spoon-shaped nails)
• Atrophic glossitis (tongue atrophy)

Plummer-Vinson syndrome represents severe chronic iron deficiency with the triad of iron deficiency anemia, esophageal webs, and atrophic glossitis. This carries increased risk of esophageal carcinoma and must be monitored closely.

Treatment:

• Oral ferrous sulfate 325 mg every 48 hours (GI upset limits daily dosing)
• Pair with vitamin C to enhance absorption
• IV iron formulations available for severe deficiency, malabsorption, or intolerance to oral therapy
• Expect reticulocyte response in 3-7 days, Hgb improvement in 3-6 weeks
• Identify and treat underlying cause (GI bleeding, poor dietary intake, malabsorption)

Thalassemia

Thalassemias result from genetic deletions or mutations affecting globin chain production, leading to imbalanced hemoglobin synthesis. Two main types exist:

Alpha-thalassemia - deletions on chromosome 16 affecting alpha-globin genes: - Prevalence in Southeast Asian, Mediterranean, and African populations - Severity ranges from silent carrier to Hb H disease to hydrops fetalis - Diagnosis requires careful clinical suspicion; gene testing confirms mutations

Beta-thalassemia - mutations on chromosome 11 affecting beta-globin genes: - Prevalence in Mediterranean, African, and Asian populations - Thalassemia major (homozygous) presents in infancy with severe hemolytic anemia - Thalassemia minor (heterozygous) presents as mild microcytic anemia - Hemoglobin electrophoresis shows elevated HbA2 and/or HbF

Laboratory differentiation from iron deficiency: - Normal or elevated serum iron and ferritin (from chronic transfusions) - Normal or low TIBC - Normal or increased RBC count (contrasts with iron deficiency)

Anemia of Chronic Disease

This represents the second most common cause of anemia after iron deficiency. Chronic inflammation impairs iron utilization and erythropoietin responsiveness.

Associated conditions:

• Autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus)
• Chronic infections (tuberculosis, osteomyelitis, endocarditis)
• Malignancies (both from tumor burden and chemotherapy)
• End-stage renal disease

Laboratory pattern:

• Low serum iron, low TIBC, normal or elevated ferritin
• Contrasts with iron deficiency (which shows high TIBC)
• Generally mild to moderate severity
• May be normocytic or microcytic

Management:

• Treat underlying disease
• Erythropoiesis-stimulating agents for renal disease or chemotherapy-induced anemia
• Iron supplementation often unhelpful in pure anemia of chronic disease

Sideroblastic Anemia

Rare disorder characterized by abnormal iron accumulation in mitochondria, creating pathognomonic findings on bone marrow examination.

Microscopic features:

• Pappenheimer bodies - iron-laden mitochondria visible on bone marrow biopsy
• Ring sideroblasts - myeloblasts with iron-laden rings surrounding the nucleus
• Typically presents with microcytic or normocytic anemia

Causes include:

• Myelodysplastic syndrome (most common acquired form)
• Copper deficiency
• Medications (isoniazid, chloramphenicol, linezolid)
• Alcohol abuse
• Idiopathic or X-linked inheritance

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Normocytic Anemia (MCV 80-100)

Aplastic Anemia

Aplastic anemia represents bone marrow failure with severely reduced hematopoietic progenitor cells. The hallmark is pancytopenia with absent reticulocyte response.

Laboratory findings:

• Low hemoglobin, low platelet count, low WBC
• Reticulocyte count inappropriately low (not elevated despite anemia)
• Peripheral smear shows normal RBC morphology
• Bone marrow biopsy shows hypocellular marrow with fat spaces

Common etiologies:

• Idiopathic (most common; autoimmune mechanism suspected)
• Radiation or chemotherapy exposure
• Viral infections (EBV, parvovirus B19, HIV)
• Medications (chloramphenicol, NSAIDs, anticonvulsants, sulfonamides)
• Autoimmune diseases

Management:

• Supportive care with transfusions
• Immunosuppressive therapy (ATG, cyclosporine)
• Hematopoietic stem cell transplantation if available and younger patient
• Avoid unnecessary transfusions that may allo-sensitize before transplant

Hemolytic Anemia

Hemolytic anemias result from shortened RBC lifespan (normal ~120 days). Bone marrow appropriately increases erythropoiesis, creating elevated reticulocyte count.

Laboratory hallmarks of hemolysis:

• Elevated reticulocyte count (>2%)
• Elevated LDH (from RBC destruction)
• Low haptoglobin (consumed binding free hemoglobin)
• Elevated indirect bilirubin (from heme degradation)
• Direct antiglobulin test (Coombs) positive or negative depending on mechanism

Immune-mediated hemolysis (Coombs positive):

• Warm autoimmune hemolytic anemia - IgG antibodies bind RBCs optimally at body temperature
• Most common autoimmune hemolytic anemia
• Associated with systemic lupus erythematosus, chronic lymphocytic leukemia, lymphomas

• Treatment: corticosteroids (prednisone 1 mg/kg/day) or IVIG

• Cold agglutinin disease - IgM antibodies bind RBCs optimally at cold temperatures

• Symptoms worse in cold weather
• Associated with infections (mycoplasma, EBV) or lymphomas
• Treatment: cold avoidance, rituximab, complement inhibitors

Intrinsic RBC defects (Coombs negative hemolysis):

• G6PD deficiency - most common enzyme defect worldwide
• X-linked inheritance
• Hemolytic episodes triggered by oxidative stress (fava beans, sulfa drugs, infections, aspirin)
• Peripheral smear shows Heinz bodies (precipitated hemoglobin) and bite cells (phagocytes removing Heinz bodies)

• Diagnosis: G6PD enzyme assay; avoid hemolytic triggers

• Sickle cell disease - polymerization of hemoglobin S

• Vaso-occlusive crises from RBC sickling in small vessels
• Acute chest syndrome (pleuritic chest pain, infiltrate)
• Splenic sequestration (sudden Hgb drop, splenomegaly, shock)
• Peripheral smear shows Howell-Jolly bodies (nuclear remnants from hyposplenism)

• Treatment: hydroxyurea, transfusions for crises, penicillin prophylaxis

• Hereditary spherocytosis - RBC membrane protein defects

• Spherical RBC shape with osmotic fragility (lyse in hypotonic solutions)
• Family history common

• Treatment: folic acid supplementation, splenectomy if severe

• Paroxysmal nocturnal hemoglobinuria (PNH) - acquired complement-mediated hemolysis

• Absent CD55 and CD59 (complement regulatory proteins) on blood cells
• Diagnosis: flow cytometry testing for CD55/CD59
• Thrombosis risk; use anticoagulation
• Treatment: complement inhibitors (eculizumab, pegcetacoplan)

Extrinsic hemolysis (Coombs negative):

• Microangiopathic hemolytic anemia (MAHA) - RBC fragmentation in small vessels
• Schistocytes (fragmented RBCs) on peripheral smear
• Associated with DIC, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura

• See separate sections on these conditions

• Hypersplenism - pooling and destruction in enlarged spleen

• Splenomegaly from cirrhosis, leukemia, lymphoma, or infection
• Hemolysis less prominent than thrombocytopenia

• Treatment: splenectomy if severe

• Infection-mediated hemolysis - direct parasitic damage or immune activation

• Malaria, clostridial infection, sepsis
• Treatment: antibiotics and supportive care

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Macrocytic Anemia (MCV >100)

Megaloblastic Anemias

Megaloblastic anemias result from impaired DNA synthesis affecting all rapidly dividing cells. RBC precursors become dysplastic, producing larger RBCs with asynchronous maturation.

Laboratory features:

• Hypersegmented neutrophils - >5 nuclear lobes (normal is 3-5)
• Pancytopenia possible
• Elevated LDH and elevated indirect bilirubin (ineffective erythropoiesis)
• Bone marrow shows megaloblastic changes

Vitamin B12 deficiency:

• Reduced B12 impairs methylation reactions essential for DNA synthesis
• Laboratory findings: elevated methylmalonic acid, elevated homocysteine
• Clinical manifestations include subacute combined degeneration:
• Paresthesias (peripheral neuropathy)
• Weakness and ataxia (posterior column dysfunction)
• Cognitive changes, dementia if prolonged

• Optic neuropathy

• Common causes:

• Pernicious anemia (autoimmune destruction of gastric parietal cells producing intrinsic factor)
• Gastrectomy or gastric bypass surgery
• Chronic metformin or proton pump inhibitor use
• Vegan diet

• Terminal ileum disease (Crohn's disease, celiac sprue)

• Treatment: B12 1 mg IM daily for 7 days, then weekly for 4-8 weeks, then monthly lifelong

• Oral B12 supplements (cyanocobalamin) less reliable due to absorption issues
• Neurologic symptoms may not fully reverse if long-standing

Folate deficiency:

• Folate essential for single-carbon transfer reactions and DNA synthesis
• Laboratory findings: low serum folate, elevated homocysteine, normal methylmalonic acid (unlike B12 deficiency)
• No neurologic manifestations (distinguishes from B12 deficiency)
• Common causes:
• Malnutrition
• Alcoholism
• Methotrexate or trimethoprim use
• Pregnancy

• Hemolytic anemias (increased consumption)

• Treatment: Folate 1 mg orally daily for 1-4 months

B12 vs. Folate Deficiency

Never give folate supplementation to a patient with unrecognized B12 deficiency. Folate can "mask" the hematologic manifestations of B12 deficiency while neurologic damage continues to progress. Always check B12 level first if suspecting either deficiency.

Non-Megaloblastic Macrocytic Anemias

Liver disease: - Cirrhosis and hepatitis impair thrombopoietin production and cause portal hypertension - Hypersplenism contributes to anemia - RBC membrane abnormalities create macrocytic indices - Treatment: address underlying liver disease

Alcoholism: - Direct toxic effect on bone marrow - Folate depletion from poor nutrition - May also cause sideroblastic changes - Treatment: abstinence, nutritional support, folate supplementation

Reticulocytosis: - Elevated reticulocyte count creates higher average RBC volume (reticulocytes larger than mature RBCs) - Occurs in response to hemolysis or acute blood loss - MCV normalizes as reticulocytes mature; this is not true pathologic macrocytosis

Hypothyroidism: - Decreased metabolic rate slows erythropoiesis - Creates mild macrocytosis - Treatment: thyroid hormone replacement

Myelodysplastic syndromes: - Dysplastic changes in hematopoietic precursors - Macrocytic anemia common - Risk of progression to acute leukemia - Treatment: supportive care, azacitidine for higher-risk MDS

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Thrombocytopenia

Clinical Thresholds

When evaluating thrombocytopenia, the absolute platelet count guides assessment of bleeding and thrombosis risk:

Platelet Count	Spontaneous Bleeding Risk	Clinical Significance
>100 K/μL	Minimal	Normal hemostasis
50-100 K/μL	Low; only with major trauma	Acceptable for most procedures
20-50 K/μL	Minor bleeding with trauma	Increased concern with invasive procedures
<20 K/μL	Spontaneous bleeding possible	Major hemorrhage risk
<10 K/μL	Significant spontaneous bleeding	Life-threatening; transfuse immediately

Thrombotic Thrombocytopenia Alert

Certain conditions cause thrombocytopenia with paradoxical thrombosis risk:

• HIT (Heparin-Induced Thrombocytopenia) - prothrombotic state despite low platelets
• Antiphospholipid syndrome - thrombosis despite thrombocytopenia
• DIC - simultaneous coagulation consumption
• TTP - microthrombi formation
• PNH - high thromboembolism risk

These require specific evaluation and anticoagulation, not just transfusion support.

Diagnostic Approach

The workup of new-onset thrombocytopenia should distinguish decreased production from increased destruction or sequestration:

Initial investigations:

• CBC with differential - confirm thrombocytopenia, assess hemoglobin and WBC
• Peripheral blood smear - rule out pseudothrombocytopenia (platelet clumping), assess RBC/WBC morphology
• HIV and HCV serology - common infectious causes
• Direct antiglobulin test (Coombs) - assess for concurrent hemolytic anemia

Additional testing based on clinical context:

• Viral titers (EBV, CMV, HSV) - if infectious cause suspected
• Flow cytometry - assess for immune-mediated destruction, PNH
• ANA and antiphospholipid antibodies - autoimmune/vasculitis assessment
• LDH, haptoglobin, indirect bilirubin, schistocytes - hemolysis markers
• PT, PTT, fibrinogen, D-dimer - coagulation assessment for DIC
• Bone marrow biopsy - if production defect suspected or diagnosis unclear

Immune Thrombocytopenia (ITP)

ITP represents autoimmune destruction of platelets by circulating IgG antibodies targeting platelet surface glycoproteins (usually GP IIb/IIIa or GP Ib/IX).

Diagnostic criteria:

• Diagnosis of exclusion after ruling out secondary causes
• Isolated thrombocytopenia (no other cytopenias)
• Normal bone marrow with adequate megakaryocytes
• Absence of clinical splenomegaly
• No family history of thrombocytopenia

Classification:

• Newly diagnosed - <3 months duration
• Persistent - 3-12 months duration
• Chronic - >12 months duration

Treatment approach:

• Mild asymptomatic thrombocytopenia (>20 K) - observation
• Symptomatic or platelets <20 K:
• First-line: Corticosteroids (prednisone 1 mg/kg/day) or IVIG (2 g/kg over 3-5 days)
• Response rates: 70-80% with steroids, 80-90% with IVIG

• IVIG preferred if rapid platelet elevation needed (more rapid onset)

• Refractory or relapsed disease:

• Rituximab (monoclonal anti-CD20 antibody)
• Splenectomy (70% response rate; effect lasts 5+ years in 80%)
• Thrombopoietin receptor agonists (romiplostim, eltrombopag)

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Microangiopathic Hemolytic Anemia (MAHA)

Hemolytic Uremic Syndrome (HUS)

HUS results from Shiga toxin produced by certain bacteria (most commonly Escherichia coli O157:H7, also Shigella). The toxin damages microvascular endothelium, triggering the characteristic triad:

Classic triad:

1. Thrombocytopenia - platelet consumption in microthrombi
2. Microangiopathic hemolytic anemia - mechanical fragmentation of RBCs passing through narrowed vessels
3. Acute renal failure - glomerular capillary damage

Laboratory findings:

• Schistocytes on peripheral smear (fragmented RBCs)
• Elevated creatinine and oliguria (renal dysfunction)
• Normal PT/PTT/fibrinogen (distinguishes from DIC)
• Elevated LDH, low haptoglobin, elevated indirect bilirubin (hemolysis markers)

Clinical presentation:

• Often follows diarrheal illness (often bloody diarrhea from Shiga toxin enteritis)
• Younger children most severely affected
• Fever may precede hemolysis and thrombocytopenia
• Neurologic symptoms less prominent than in TTP

Management:

• Supportive care is cornerstone of therapy
• Fluid management and renal replacement therapy as needed
• DO NOT routinely transfuse platelets (may worsen thrombosis)
• Prognosis excellent in children; worse in adults
• Antibiotics for underlying infection (though post-diarrheal HUS prognosis often good regardless)

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Thrombotic Thrombocytopenic Purpura (TTP)

TTP results from severely deficient ADAMTS13 activity (either congenital or from acquired inhibitory antibodies). Uncleaved vWF multimers cause widespread platelet aggregation and microvascular thrombosis.

Classic pentad (full pentad rare; thrombocytopenia + MAHA sufficient for diagnosis):

1. Fever - occurs in 25-50%
2. Microangiopathic hemolytic anemia - mechanical fragmentation
3. Thrombocytopenia - severe, often <20 K
4. Renal dysfunction - occurs in ~50% (usually mild compared to HUS)
5. Neurologic symptoms - most distinctive feature (50-60%)
6. Fluctuating mental status, confusion, delirium
7. Seizures
8. Focal neurologic deficits (stroke-like)
9. Often neurologic symptoms precede other manifestations

Laboratory findings:

• Schistocytes on smear
• Severe thrombocytopenia
• Severe hemolysis (very elevated LDH, very low haptoglobin)
• Normal PT/PTT/fibrinogen (CRITICAL distinction from DIC)
• ADAMTS13 activity <10% confirms diagnosis

Management - URGENT PLASMA EXCHANGE:

TTP Treatment Protocol

IMMEDIATE actions:

• Start plasma exchange within hours of diagnosis
• Goal: remove autoantibodies against ADAMTS13 and replace enzyme activity
• Continue daily plasma exchange until platelet recovery (may require 5-15 days)
• DO NOT GIVE PLATELETS or FFP unless life-threatening hemorrhage (may worsen thrombosis)
• Add corticosteroids (methylprednisolone 1 g IV daily) as adjunctive therapy

Expected response:

• Platelet recovery within 3-5 days with appropriate therapy
• Failure to respond to plasma exchange suggests alternative diagnosis
• Rituximab or other immunotherapy for ADAMTS13 inhibitor-mediated cases

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Disseminated Intravascular Coagulation (DIC)

DIC represents pathologic activation of the coagulation cascade in response to severe systemic illness. Widespread fibrin formation consumes coagulation factors and platelets while simultaneously activating fibrinolysis, creating a bleeding diathesis.

Pathophysiology:

Tissue damage or endotoxin triggers Tissue Factor exposure → activation of the extrinsic pathway → widespread thrombin generation → fibrin clot formation throughout the microvasculature → consumption of factors, fibrinogen, and platelets → compensatory fibrinolysis → D-dimer elevation

Triggering conditions:

• Massive trauma (especially head trauma)
• Sepsis (bacterial endotoxins most common)
• Malignancies (especially acute leukemias, prostate cancer)
• Obstetric complications (placental abruption, amniotic fluid embolism, retained dead fetus syndrome)
• Severe hemolysis
• Acute liver failure
• Snake bite
• Heatstroke

Laboratory diagnostic criteria (at least 2 required):

• Thrombocytopenia (usually moderate, platelet count 50-100 K)
• Low fibrinogen (<100 mg/dL) - consumed by excessive clotting
• Elevated PT/PTT - consumed factors
• Elevated D-dimer - from active fibrinolysis
• Schistocytes on peripheral smear - mechanical hemolysis

Clinical presentation:

• Acute DIC - fulminant bleeding (cutaneous, GI, pulmonary)
• Chronic DIC - milder consumptive coagulopathy (seen with malignancies)
• Microvascular thrombosis causing organ dysfunction
• Renal failure, respiratory distress, altered mental status

Management:

• Treat underlying cause - source control, antibiotics for sepsis, delivery for obstetric DIC
• Supportive transfusion:
• Platelets to maintain >50 K
• FFP to replace consumed factors
• Cryoprecipitate (goal fibrinogen >100 mg/dL) - fibrinogen depleted most rapidly

• Packed RBCs for anemia from both bleeding and hemolysis

• Anticoagulation considerations - controversial; heparin sometimes used to prevent further consumption, but bleeding risk prohibits routine use

• Monitor closely - recheck CBC, coagulation studies, fibrinogen q6-12h during acute phase

DIC vs. TTP Distinction

Both present with thrombocytopenia and schistocytes, but:

• DIC: Prolonged PT/PTT, low fibrinogen, high D-dimer → coagulation activation + fibrinolysis
• TTP: Normal PT/PTT/fibrinogen → normal coagulation studies, ADAMTS13 deficiency

TTP demands plasma exchange; DIC demands treating underlying cause.

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Heparin-Induced Thrombocytopenia (HIT)

HIT represents a paradoxical prothrombotic state triggered by antibodies against the heparin-platelet factor 4 (PF4) complex. Despite thrombocytopenia, patients face high risk of thrombosis.

Pathophysiology

Heparin exposure causes some patients to develop IgG antibodies against complexes of heparin and platelet factor 4 (a protein released from platelet granules). These immune complexes bind to platelet Fc receptors, triggering platelet activation, microthrombi formation, and paradoxically severe thromboembolism despite low platelet counts.

4Ts Scoring System

The 4Ts score stratifies HIT probability and guides initial management decisions:

Factor	2 Points	1 Point	0 Points
Timing of platelet drop	Day 5-10 post-heparin	Day >10 or <4 (if re-exposed)	Day <4 (no prior heparin)
Magnitude of platelet decline	>50% drop, not below 100K	30-50% drop or nadir 100-150K	<30% drop or nadir >150K
Thrombosis	New thrombosis or thromboembolism	Progressive or recurrent thrombosis during heparin	None
alTernative causes	None apparent	Possible	Definite alternative diagnosis

Risk stratification:

• Score 4-5: Intermediate probability - further testing warranted
• Score 6-8: High probability - immediate action required

Diagnosis and Testing

• Clinical diagnosis based on 4Ts score
• HIT antibody assay (ELISA) - sensitive but not specific
• Platelet aggregation study - more specific; confirms functional platelet activation
• Serotonin release assay - gold standard; detects antibodies causing platelet activation

Management

HIT Management Principles

IMMEDIATELY upon HIT suspicion:

• STOP all heparin products (including heparin flushes, heparin-bonded catheters)
• Start direct thrombin inhibitor: argatroban (preferred), lepirudin, or fondaparinux
• DO NOT use warfarin monotherapy (risk of warfarin-induced skin necrosis from Protein C depletion)

Transition to warfarin:

• Bridge with direct thrombin inhibitor until INR 2-3 × 24 hours
• Then discontinue direct thrombin inhibitor and continue warfarin monotherapy

Duration of anticoagulation:

• If thrombosis occurred: ≥3-6 months
• If no thrombosis: 1-3 months

Lifelong consideration:

• Permanent avoidance of all heparin products (unfractionated heparin, LMWH)
• Document in medical record
• Patient should wear medical alert bracelet

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Transfusion Management

Transfusion Indications

Blood Product	Indication	Target Level	Notes
Packed Red Blood Cells	Symptomatic anemia or acute hemorrhage	Hgb ~7-10 g/dL depending on clinical context	1 unit raises Hgb ~1 g/dL, Hct ~3%
Platelets	<10 K always; <20 K if bleeding; <50 K before surgery	Maintain >20 K if active bleeding	1 unit raises platelets ~30 K (depends on patient factors)
Fresh Frozen Plasma	Coagulopathy with bleeding, INR reversal, TTP	Depends on indication	Contains all clotting factors
Cryoprecipitate	Low fibrinogen, hyperfibrinolysis	Goal fibrinogen >100 mg/dL	Rich in fibrinogen and Factor XIII

Massive Transfusion Protocol

When patients require >3 units packed RBCs in 24 hours, activate massive transfusion protocol to avoid dilutional coagulopathy:

Empiric ratio approach:

• 3:1:1 ratio - 3 units packed RBCs : 1 unit FFP : 1 six-pack platelets
• Continue this ratio until bleeding controlled
• Recheck CBC, PT/PTT, fibrinogen after every 10 units pRBC

Monitoring parameters:

• Serum ionized calcium - transfusions contain citrate anticoagulant that can chelate calcium
• Core temperature - massive transfusion of cold blood causes hypothermia and coagulopathy
• Lactate - tissue hypoxia from inadequate resuscitation
• Hemoglobin/hematocrit
• Coagulation studies (PT, PTT, fibrinogen, D-dimer)

Transfusion Reactions

Febrile Transfusion Reaction

Fever developing during or shortly after transfusion (usually due to WBC antibodies or cytokine release):

• Stop transfusion immediately
• Send blood back to blood bank for testing
• Assess for sepsis
• Give acetaminophen and diphenhydramine
• May resume transfusion after excluding serious complications (sepsis, hemolysis)

Anaphylactic Reaction

Severe immediate reaction (usually in IgA-deficient patients transfused with IgA-containing products):

Immediate management:

• Stop transfusion immediately
• Send blood and patient samples to blood bank
• Give acetaminophen + diphenhydramine + methylprednisolone IV
• Epinephrine 0.3-0.5 mg IM every 10-15 minutes if true anaphylaxis with hypotension
• Secure airway if laryngeal edema develops; intubate early to avoid difficult airway
• Avoid repeat transfusion with standard products (use IgA-depleted products in future)

Transfusion-Related Acute Lung Injury (TRALI)

Immune-mediated pulmonary edema developing during or within 6 hours of transfusion. Represents one of the most serious transfusion complications.

Clinical presentation:

• Acute respiratory distress (within minutes to hours)
• Hypoxemia
• Bilateral infiltrates on chest X-ray (pulmonary edema)
• Hypertension or hypotension
• Fever, chills

Management:

• STOP transfusion immediately
• Send blood to blood bank for testing
• Obtain CXR - shows bilateral infiltrates consistent with ARDS
• Rule out volume overload or other causes of acute respiratory distress
• Methylprednisolone IV as adjunctive therapy
• Oxygen supplementation; support oxygenation aggressively
• Intubate early with sustained PEEP rather than delaying
• Most patients recover within 48-96 hours with supportive care
• Avoid repeat transfusion from implicated donors

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Key Clinical Pearls

Hematology Practice Tips

1. Reticulocyte count is your friend - appropriately elevated in hemolysis, appropriately low in aplastic anemia; tells you if marrow is responding

2. Always check a smear - computerized WBC counts miss blasts, abnormal morphology, clues to diagnosis

3. Mixing study timing matters - perform immediately; delays cause in vitro factor activation/degradation

4. PT/PTT patterns guide diagnosis:

5. Isolated PT prolongation = Factor VII deficiency (rarest single factor deficiency)
6. Isolated PTT prolongation = Intrinsic pathway defect (very common)

7. Both prolonged = Common pathway, vitamin K deficiency, or severe deficiency of multiple factors

8. Warfarin reversal is time-dependent - vitamin K takes 12-24 hours; use KCentra for urgent bleeding

9. DOACs are more reversible than you think - andexanet alfa and idarucizumab are specific antidotes with good efficacy

10. HIT is prothrombotic, not just thrombocytopenic - stop heparin immediately, start direct thrombin inhibitor, avoid platelets/FFP

11. TTP demands plasma exchange NOW - mortality >90% untreated; >90% survive with plasma exchange

12. Never assume bleeding is from low platelets - coagulopathy and platelet dysfunction matter too

13. Document anticoagulation holding times - surgery requires specific lead times; don't just restart on postop day 1

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Quick Reference Tables

Hemostasis Laboratory Values

Test	Normal Range	Interpretation
PT (INR)	0.8-1.1 (INR)	Prolongation suggests Factors II, V, VII, X or fibrinogen deficiency
aPTT	25-35 seconds	Prolongation suggests intrinsic pathway or common pathway defect
Fibrinogen	200-400 mg/dL	Low in DIC, liver disease, massive transfusion
Platelet Count	150-400 K/μL	<50 K increases bleeding risk; <20 K high spontaneous bleeding risk
D-dimer	<500 ng/mL	Elevated in DIC, VTE, sepsis, recent surgery
Haptoglobin	30-200 mg/dL	Low in hemolysis (consumed binding free Hgb)
LDH	140-280 IU/L	Elevated in hemolysis, liver disease, myocardial infarction
Indirect Bilirubin	0.1-0.3 mg/dL	Elevated in hemolysis (heme breakdown)
Reticulocyte Count	0.5-2.5%	Elevated response to anemia or hemolysis; inappropriately low in aplastic anemia

MCV-Based Anemia Classification Quick Reference

MCV Range	Likely Diagnoses	Next Step
<80 (Microcytic)	Iron deficiency, thalassemia, anemia of chronic disease, sideroblastic	Iron studies; Hgb electrophoresis if indicated
80-100 (Normocytic)	Aplastic anemia, hemolytic anemia, acute hemorrhage, chronic kidney disease	Reticulocyte count; peripheral smear; hemolysis labs
>100 (Macrocytic)	B12 deficiency, folate deficiency, liver disease, hypothyroidism, MDS	B12 and folate levels; LFTs; TSH

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Last update: April 12, 2026