Specialist Hematology Practice

Where Blood
Becomes Answers.

A single vial drawn at 7 a.m. becomes a complete narrative — clotting cascades, iron kinetics, cell morphology. For internists, oncologists, and patients who need answers.

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Diagnostic Pathways

The Presentation vs. The Workup

Each row is a clinical mystery. Click to reveal the structured diagnostic pathway — and the downloadable resource behind it.

Red Cell Disorders

Unexplained Anemia

When Hgb drops and the cause stays hidden

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Clinical PresentationDiagnostic PathwayResource

Normocytic anemia, normal reticulocyte count

Hgb 9.2 g/dL · MCV 88 fL · Retic 1.1%

Bone marrow reserve + erythropoietin axis evaluation

EPO level · Serum hepcidin · Soluble transferrin receptor

Algorithm

Diagnostic Steps

  1. 1Obtain EPO level — if inappropriately low, evaluate for CKD or endocrine suppression
  2. 2Serum hepcidin distinguishes ACD from true iron deficiency (hepcidin elevated in ACD)
  3. 3If hepcidin normal/low: evaluate for early iron deficiency with sTfR/ferritin index
  4. 4Bone marrow biopsy if cytopenias persist >6 weeks without clear etiology

Key Tests

EPO levelSerum hepcidinSoluble TfRFerritin + CRPPeripheral smear review

Clinical Pearl

Hepcidin >25 ng/mL in the setting of anemia virtually excludes true iron deficiency and points toward inflammatory suppression of erythropoiesis.

Download: Normocytic Anemia Decision Tree

Microcytic anemia, ferritin 180 ng/mL

Hgb 8.7 g/dL · MCV 72 fL · Ferritin 180 · TIBC low

Thalassemia vs. ACD vs. Sideroblastic differentiation

Hemoglobin electrophoresis · Zinc protoporphyrin · Bone marrow iron stain

PDF

Diagnostic Steps

  1. 1Elevated ferritin with microcytosis rules out simple IDA — consider thalassemia trait first
  2. 2Hemoglobin electrophoresis: HbA2 >3.5% confirms beta-thalassemia trait
  3. 3Zinc protoporphyrin elevated in lead poisoning and sideroblastic anemia
  4. 4Bone marrow with ring sideroblasts (>15% of erythroblasts) = sideroblastic anemia

Key Tests

Hemoglobin electrophoresisZinc protoporphyrinSerum leadBone marrow iron stainReticulocyte hemoglobin

Clinical Pearl

A ferritin >100 with microcytosis in a patient of Mediterranean or Southeast Asian descent should prompt Hgb electrophoresis before any iron supplementation.

Download: Microcytic Anemia with Elevated Ferritin Workup

Macrocytic anemia, B12 borderline normal

Hgb 10.1 g/dL · MCV 104 fL · B12 248 pg/mL

Functional B12 deficiency assessment

Methylmalonic acid · Homocysteine · Anti-IF antibodies

Reference Card

Diagnostic Steps

  1. 1Serum B12 200–400 pg/mL is a diagnostic gray zone — MMA and homocysteine required
  2. 2Elevated MMA (>271 nmol/L) confirms functional B12 deficiency even with "normal" serum level
  3. 3Anti-intrinsic factor antibodies: 50–70% sensitivity but >95% specific for pernicious anemia
  4. 4Trial of B12 replacement with reticulocyte response at day 7 is both diagnostic and therapeutic

Key Tests

Methylmalonic acidHomocysteineAnti-IF antibodyAnti-parietal cell AbReticulocyte count

Clinical Pearl

Methylmalonic acid is the most sensitive marker of intracellular B12 deficiency. A normal MMA in macrocytic anemia redirects the workup to folate, liver disease, or hypothyroidism.

Download: B12 Borderline Workup Reference Card
Coagulation

Recurrent Thrombosis & Unexplained Bleeding

Beyond the standard coag panel

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Clinical PresentationDiagnostic PathwayResource

Recurrent DVT, age 34, no provocation

2nd unprovoked DVT · Family history of clotting · On OCP

Comprehensive thrombophilia workup with timing protocol

Factor V Leiden · Prothrombin G20210A · Protein C/S/Antithrombin · Antiphospholipid panel

PDF

Diagnostic Steps

  1. 1Do NOT test within 3 months of acute thrombosis — acute phase reactants falsely elevate Protein C and S
  2. 2Warfarin reduces Protein C and S — hold 2 weeks before testing; DOAC affects functional assays
  3. 3Antiphospholipid syndrome requires 2 positive tests ≥12 weeks apart (lupus anticoagulant, anticardiolipin, anti-β2GP1)
  4. 4Factor V Leiden R506Q and Prothrombin G20210A by PCR — not affected by anticoagulation timing

Key Tests

Factor V Leiden (PCR)PT G20210A (PCR)Protein C activityProtein S free antigenAntithrombin activityLupus anticoagulant screenAnticardiolipin IgG/IgMAnti-β2GP1

Clinical Pearl

Lupus anticoagulant testing is invalid while on any anticoagulant. Plan testing windows carefully — the most common error in thrombophilia workup is incorrect timing.

Download: Thrombophilia Workup Timing Guide

Easy bruising, prolonged bleeding, normal PT/PTT

Mucocutaneous bleeding · Normal PT 11s · Normal PTT 30s · Normal CBC

Platelet function and von Willebrand disease evaluation

PFA-100 · VWF antigen · VWF activity (ristocetin cofactor) · VWF multimers

Algorithm

Diagnostic Steps

  1. 1PFA-100 closure time: sensitive screening for VWD and platelet function defects (not affected by aspirin in VWD)
  2. 2VWF:Ag and VWF:RCo ratio <0.6 suggests VWD type 2 (qualitative defect)
  3. 3VWF multimer analysis distinguishes type 2A (absent high/intermediate multimers) from 2B and 2M
  4. 4Platelet aggregation studies (ADP, collagen, epinephrine, ristocetin) if VWD excluded

Key Tests

PFA-100 (collagen/ADP)VWF antigenVWF ristocetin cofactorVWF multimersFactor VIII activityPlatelet aggregation

Clinical Pearl

VWF levels are blood group dependent — type O individuals have VWF levels 25% lower than type A. Always interpret VWF antigen relative to ABO blood group before diagnosing type 1 VWD.

Download: VWD Subtype Classification Algorithm
Smear & Morphology

Abnormal Peripheral Smear

Findings that demand a second look

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Clinical PresentationDiagnostic PathwayResource

Circulating blasts, WBC 28,000, no prior history

12% blasts on smear · WBC 28k · Hgb 9.1 · Plt 48k

Acute leukemia vs. accelerated phase MPN workup

Flow cytometry immunophenotyping · Bone marrow biopsy · Cytogenetics + NGS panel

Algorithm

Diagnostic Steps

  1. 1Flow cytometry on peripheral blood within 24 hours — do not wait for bone marrow
  2. 2CD34+, CD117+, MPO+ → AML lineage; TdT+, CD19+, CD10+ → B-ALL
  3. 3Bone marrow aspirate and biopsy for morphology, cytogenetics (FISH + karyotype), and NGS
  4. 4NGS 54-gene myeloid panel: FLT3-ITD, NPM1, IDH1/2, RUNX1, TP53 — critical for prognosis and targeted therapy

Key Tests

Peripheral blood flow cytometryBone marrow aspirate + biopsyKaryotype + FISHNGS myeloid panelLDH · Uric acid · Phosphorus (TLS risk)

Clinical Pearl

FLT3-ITD status must be known before induction in AML — midostaurin is added to 7+3 in FLT3-mutated AML. This result changes day-1 treatment decisions.

Download: Blast Identification & Triage Protocol

Teardrop cells + nucleated RBCs + leukoerythroblastic picture

Dacrocytes · nRBCs · Left shift · Splenomegaly on exam

Myelofibrosis vs. bone marrow infiltrative process

JAK2 V617F · CALR · MPL mutations · Bone marrow trephine biopsy

PDF

Diagnostic Steps

  1. 1Leukoerythroblastic picture = bone marrow stress — always requires bone marrow evaluation
  2. 2JAK2 V617F positive in ~95% of PV, ~55% of ET and PMF
  3. 3CALR exon 9 mutation in ~25% of JAK2-negative ET and PMF
  4. 4Bone marrow trephine: reticulin/collagen fibrosis grading (MF-0 to MF-3) defines disease stage

Key Tests

JAK2 V617F (allele burden %)CALR exon 9MPL W515L/KBone marrow trephine + reticulinLDH · Uric acidErythropoietin level

Clinical Pearl

JAK2 V617F allele burden >50% correlates with bone marrow fibrosis and splenomegaly severity. Serial monitoring of allele burden can track disease progression or response to ruxolitinib.

Download: Leukoerythroblastic Reaction Workup
Iron Metabolism

Elevated Ferritin — The Diagnostic Trap

When the number is high but the story is complex

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Clinical PresentationDiagnostic PathwayResource

Ferritin 1,800 ng/mL, transferrin saturation 52%

Male · Age 42 · Fatigue · Elevated LFTs · Bronze skin

Hereditary hemochromatosis evaluation and organ staging

HFE gene mutation (C282Y/H63D) · Liver MRI (R2* iron quantification) · Hepatology referral threshold

PDF

Diagnostic Steps

  1. 1HFE C282Y homozygosity + TSAT >45% confirms HH — no further genetic testing needed
  2. 2Liver MRI with R2* sequence quantifies hepatic iron concentration non-invasively
  3. 3Liver biopsy indicated if: ferritin >1000 + abnormal LFTs + age >40 (fibrosis risk)
  4. 4Phlebotomy goal: ferritin <50 ng/mL — typically requires weekly phlebotomy for 1–2 years

Key Tests

HFE C282Y/H63D genotypeTransferrin saturationLiver MRI R2*LFTs + GGTFasting glucose (bronze diabetes)Echocardiogram (cardiac iron)

Clinical Pearl

Transferrin saturation >45% on a fasting morning specimen is the most sensitive screening test for HH. Ferritin alone is insufficient — it rises late and is confounded by inflammation.

Download: Hemochromatosis Staging & Management Guide

Ferritin 3,400 ng/mL, normal TSAT, fever, cytopenias

Ferritin 3,400 · TSAT 28% · WBC 2.1k · Plt 55k · Splenomegaly

Hemophagocytic lymphohistiocytosis evaluation

HScore calculation · Bone marrow biopsy · NK cell activity · sCD25 · Triglycerides · Fibrinogen

Algorithm

Diagnostic Steps

  1. 1HScore ≥169 has 93% sensitivity and 86% specificity for HLH
  2. 2Bone marrow biopsy: hemophagocytosis (macrophages engulfing RBCs, WBCs, platelets)
  3. 3sCD25 (soluble IL-2 receptor) >2400 U/mL supports HLH diagnosis
  4. 4NK cell cytotoxicity <10% of normal: functional assay required, not just NK count

Key Tests

Ferritin (serial)TriglyceridesFibrinogensCD25 (IL-2R)NK cell cytotoxicityBone marrow biopsyHScore calculation

Clinical Pearl

Ferritin >10,000 ng/mL has a 90% positive predictive value for HLH in the right clinical context. The diagnostic mistake is attributing extreme hyperferritinemia to liver disease alone without completing the HScore.

Download: HLH HScore Calculator & Diagnostic Criteria
Clinical Resources

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Specialty-matched diagnostic algorithms
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"The thrombophilia timing guide alone saved me from a workup error that would have given three false negatives. This is the resource I wish I had in fellowship."

DR

Dr. Rachel Okonkwo

Internal Medicine · Houston, TX

48h

Average time to initial interpretation

94%

Of referrals receive a definitive diagnosis within 2 weeks

12+

Years focused exclusively on hematologic disorders

Refer a Patient

When the CBC
Doesn't Add Up

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