Hematological Disorders: Comprehensive Overview
Definition and Scope
Hematological disorders encompass a diverse group of conditions affecting the blood, bone marrow, and lymphatic systems, including bleeding disorders, anemias, malignancies (lymphoma, leukemia, myeloma), myelodysplastic syndromes, and myeloproliferative neoplasms 1. These disorders represent the fifth most common cancer category in Britain, with approximately 38,000 new diagnoses annually, though many non-malignant conditions also fall under this umbrella 1.
Bleeding Disorders of Unknown Cause (BDUC)
Clinical Significance
BDUC represents 60-70% of patients with mild-moderate bleeding phenotypes and requires specialized hemostatic management despite completely normal laboratory testing 2. These patients demonstrate bleeding tendencies clinically indistinguishable from established disorders like von Willebrand disease or platelet function defects, yet all standard hemostatic tests return normal 2.
Diagnostic Approach
Initial Clinical Assessment
- Use the ISTH Bleeding Assessment Tool (BAT) in 100% of cases to objectively quantify bleeding symptoms, with age-dependent reference ranges (normal <3 in children, <6 in adult females, <4 in adult males) 3, 2
- Obtain detailed family history in 98% of evaluations, recognizing that inheritance patterns may be unclear in BDUC 3, 2
- Document all medication use in 88% of cases, specifically NSAIDs and over-the-counter medications that affect hemostasis 3, 2
- Assess for hypermobility using Beighton score in 55% of cases, as joint hypermobility associates with bleeding symptoms 3, 2
First-Line Laboratory Testing
The following tests should be performed universally as initial screening 2:
- Activated partial thromboplastin time (APTT) - 100% of specialists perform this 2
- Prothrombin time (PT) - 100% of specialists perform this 2
- Fibrinogen levels (Clauss method) - 90% perform as first-line 2
- Von Willebrand factor antigen and function - 84% perform initially 2
- Factor VIII, IX, and XI assays - 62% perform as first-line 2
- Full blood count - 65% perform initially 3, 2
- Ferritin/iron studies - 69% perform as first-line, critical given high prevalence of iron deficiency in bleeding disorders 3, 2
- ABO blood group - 70% perform, though group-specific VWF reference ranges are not recommended 3, 2
- Thyroid function testing - 45% perform initially to exclude hypothyroidism as a correctable cause 3, 2
Common pitfall: Only 69% check ferritin despite iron deficiency being extremely common in bleeding disorders; this must be assessed universally 3.
Second-Line Testing (When First-Line Normal)
Perform the following when initial testing is unrevealing but bleeding history remains convincing 2:
- Factor II, V, VII, X assays - 52-55% perform as second-line 2
- Factor XIII assay - 60% perform as second-line 2
- Platelet function testing (light transmission aggregometry) - 60% perform as second-line, recognizing this is resource-intensive and requires standardized methodology 3, 2
- Platelet flow cytometry - 42% perform as second-line 2
- Fibrinolysis assays - 38% perform as second-line 2
- Thrombin generation assay - 28% perform as second-line 2
- Genetic testing - 48% perform as second-line, best employed in research settings 3, 2
Critical caveat: PFA 100/200 is performed by 37% but has limited sensitivity for inherited platelet function defects and VWD 3.
Diagnostic Terminology
Use "Bleeding Disorder of Unknown Cause" (BDUC) as the standardized diagnostic label when patients have convincing bleeding history with normal hemostatic testing 3. Alternative terms include "Unclassified bleeding disorder" (31% use), "Bleeding of unknown cause" (16%), or "Undiagnosed bleeding disorder" (8%), but BDUC is preferred for international consistency 3.
Register 75% of BDUC patients formally to ensure access to hemostatic care and enable future research 3.
Management of BDUC
Surgical Prophylaxis
Minor Surgery
Tranexamic acid (TXA) is the preferred prophylactic agent, used by 79% of specialists (72% as monotherapy, 7% combined with desmopressin) 3, 2. TXA is inexpensive, widely available, and effective across multiple bleeding scenarios 3.
- 10% advocate no prophylaxis with treatment only if bleeding occurs 3
- If bleeding occurs during minor surgery, use desmopressin (DDAVP) as first-line (56% overall: 29% alone, 27% with TXA) or platelets (16%) 3
- For refractory bleeding, use recombinant FVIIa (rFVIIa) as second-line (30% use), followed by FFP (25%), platelets (37%), or cryoprecipitate (14%) 3
Major Surgery
TXA remains first-line prophylaxis, used by 91% of specialists (59% alone, 32% combined with DDAVP) 3, 2. Only 2% advocate expectant management for major surgery 3.
- If bleeding occurs during major surgery, use platelets as first-line (48% overall: 31% alone, 17% with TXA), followed by FFP (19%) 3
- For refractory bleeding, use rFVIIa as second-line (40% use), followed by FFP (23%), platelets (19%), PCC (15%), or cryoprecipitate (13%) 3
Rationale: Platelet preference in major surgery reflects challenges of fluid restriction when DDAVP was used prophylactically 3.
Pregnancy and Delivery
TXA is used for prophylaxis in 58% of deliveries 3, 2. However, significant uncertainty exists regarding fetal precautions and regional anesthesia safety - most clinicians either recommend precautions or express uncertainty, and similarly advise against or are uncertain about maternal regional anesthesia 3.
Management of offspring: For children born to BDUC patients, 79% favor expectant management for the child's first hemostatic challenge, with only 15% advising upfront prophylaxis 3.
Heavy Menstrual Bleeding (HMB)
For HMB persisting despite combined oral contraceptive pill (COCP) 3, 2:
First-Line Treatment
- Add TXA to COCP (53% use this approach) 3
- Alternative: Discontinue COCP and insert levonorgestrel intrauterine device (IUD) (19%) or TXA alone (10%) 3
Second-Line Treatment (If First-Line Fails)
Third-Line Treatment
Critical consideration: Check serum ferritin universally, as only 69% perform this initially despite iron deficiency being common and treatable 3.
Genetic Sideroblastic Anemias
SLC25A38 Deficiency
This causes severe congenital microcytic hypochromic anemia presenting in childhood, often transfusion-dependent and clinically similar to thalassemia major 3. SLC25A38 encodes a mitochondrial inner membrane protein essential for heme synthesis 3.
Diagnosis
- Bone marrow shows ring sideroblasts 3
- Serum ferritin and transferrin saturation are elevated even before transfusions 3
- Inheritance is autosomal recessive; 26 patients reported with 20 different mutations 3
Treatment
- Symptomatic treatment consists of erythrocyte transfusions and iron chelation 3
- Hematopoietic stem cell transplantation (HSCT) is the only curative treatment, with disease-free survival in 4 of 8 transplanted patients (follow-up <5 years) 3
X-Linked Sideroblastic Anemia (XLSA)
XLSA due to ALAS2 defects is the most common genetic sideroblastic anemia, with 61 different pathogenic mutations described in 120 unrelated families since 1945 3. ALAS2 encodes erythroid-specific ALA synthase 2, critical for heme synthesis 3.
Clinical Features
- Most mutations are missense, commonly affecting catalysis or pyridoxal phosphate (vitamin B6) binding sites 3
- Female carriers can be symptomatic due to skewed X-inactivation 3
- Decreased protoporphyrin synthesis leads to reduced iron incorporation, causing microcytic anemia and mitochondrial iron loading 3
Myelodysplastic Syndromes (MDS)
Diagnostic Approach
All newly diagnosed patients should be evaluated at a center with specific hematologic competence 3.
Mandatory Investigations
- Peripheral blood smear to evaluate dysplasia and enumerate blasts 3
- Bone marrow aspirate to assess dysplasia, enumerate blasts and ring sideroblasts, and evaluate cellularity 3
- Bone marrow biopsy to assess cellularity, CD34+ cells, and fibrosis 3
- Cytogenetic analysis to detect acquired clonal chromosomal abnormalities for diagnosis and prognosis 3
Recommended Additional Testing
- Flow cytometry immunophenotyping to detect abnormalities in erythroid, myeloid, monocyte, and lymphoid compartments 3
- FISH for targeted chromosomal abnormalities when standard G-banding fails 3
Laboratory Workup
Perform the following to exclude alternative diagnoses 3:
- Complete blood count with differential
- Vitamin B12 and folate levels
- Iron studies (iron, TIBC, ferritin)
- LDH, bilirubin, haptoglobin
- Anti-HIV, anti-parvovirus B19 (in hypoplastic MDS)
- Hepatitis B and C in transfusion-dependent patients
- Paroxysmal nocturnal hemoglobinuria clone testing
- Specific genetic analyses if inherited bone marrow failure suspected 3
Critical diagnostic caveat: If only unilineage dysplasia is present without increased blasts, ring sideroblasts <15%, and no recurrent cytogenetic abnormalities, observe for 6 months and repeat bone marrow investigation before confirming MDS diagnosis 3.
Acquired Bleeding Disorders
Acquired bleeding disorders can accompany hematological, neoplastic, autoimmune, cardiovascular, or liver diseases, or arise spontaneously 4. They manifest as single factor deficiencies or complex hemostatic abnormalities 4.
Key Categories
- Acquired hemophilia A: Autoimmune disorder with inhibitory autoantibodies against factor VIII 4
- Acquired von Willebrand syndrome: Occurs in cardiovascular disorders where shear stress abnormalities destroy von Willebrand factor 4
- Liver function disorders: Comprise complex changes in pro- and anti-hemostatic factors with unpredictable clinical implications 4
Anemia in Systemic Disorders
Anemia is the most common hematological abnormality in systemic disorders 5. The bone marrow's high proliferation rate renders it highly susceptible to external factors 5.
Anemia of Chronic Disease
- Erythropoietin production is reduced and erythroid progenitor proliferation is impaired 5
- Generally alleviated by correction of the underlying disease process 5
- Always consider endocrine system status when evaluating normocytic, normochromic anemia 5
Anemia in Malignancy
Anemia in Infection
Can result from host factors, parasite factors, or treatment administered 5.