Coagulation cascade and disorders

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Pathological signs

1. Tired/dyspnea – Decreased oxygen carrying capacity of anemia
2. Mucosal pallor – Anemia
3. Glossitis/atrophic glossitis – B12 deficiency
4. Koilonychia (spoon nails) – Iron deficiency
5. Jaundice – Hemolysis, bilirubin accumulates
6. Increased risk of infection – Leukemia, lymphoma
7. Splenomegaly – Leukemia, lymphoma, portal hypertension, hemolytic anemia
8. Lymphadenopathy – Leukemia, lymphoma, infectious mononucleosis
9. Bone pain and fractures – Osteoclast activation in myeloma
10. Purpura, bruising, bleeding – Thrombocytopenia, platelet dysfunction
11. Bruising, muscle and joint bleeding – Coagulation factor deficiencies

Anemia

Etiology

1. Decreased intake of hematinics – diet, socioeconomic, dysphagia
2. Impaired absorption – Small intestine disease
3. Increased demand – Pregnancy, hemolysis
4. Impaired erythropoiesis – Aplastic anemia, leukemia
5. Hemolytic anemia – Sickle cell disease, thalassemia
6. Blood loss – Menorrhagia, GIT lesions (ulcers, carcinoma), trauma

Clinical

Fall in Hb levels below normal, therefore fall in oxygen carrying capacity leading to:

• Cardiorespiratory – Dyspnea, congestive cardia failure, murmur, angina
• Cutaneous – Pallor, brittle nails, koilonychia
• Oral – Ulcers, angular stomatitis, sore mouth
• Asymptomatic

Classification

RBC size:

• Normocytic – Aplastic anemia
• Microcytic – MCV < 80 fL – Iron deficiency, thalassemia
• Macrocytic – MCV > 100 fL – B12 and folate deficiency, aplastic anemia, alcoholics, pregnancy, malignancy, liver disease, chronic hemolysis

Etiology:

1. Blood loss:

• Acute – Trauma
• Chronic – GIT/gynecological lesions

2. Hemolytic:

• Intrinsic:
  • RBC membrane disorder – Spherocytosis, elliptocytosis, lipid defects
  • Enzyme deficiency – Glycolytic enzymes, hexose monophosphate enzymes
  • Hb synthesis disorder – Deficient Hb (thalassemia), abnormal Hb (sickle cell)
• Extrinsic:
  • Isoantibodies – Transfusion reaction, erythroblastosis fetalis
  • Autoantibodies – Drug associated, idiopathic
  • Hypercoagulation states – TTP, DIC
  • Chemical injury – lead poisoning
  • Infections – Malaria
  • Sequestration in spleen

3. Impaired RBC production:

• Stem cell defect – aplastic anemia
• CRF
• Endocrine anemia

4. Deficiency anemia – B12, folate, iron

5. Idiopathic:

• Chronic infections
• Sideroblastic anemia
• Myelophthisic anemia

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1. Iron deficiency anemia

Etiology:

• Blood loss
• Poor intake
• Poverty
• Old age
• Malabsorption
• Achlorhydria (failure to produce gastric acid)

Lab:

• ↓ Hb
• ↓ MCV
• ↓ Serum iron
• ↓ FEP (Free erythrocyte protoporphyrin)
• ↑ RDW (red blood cell distribution width)
• ↑ TIBC

Management: Iron supplements, improve diet

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2. B12 deficiency anemia

Etiology:

• Poor intake
• Poverty
• Vegetarian, vegan
• Old age
• Malabsorption:
  • Defective intrinsic factor production
  • Gastrectomy
  • Autoimmune (pernicious anemia)
  • Congenital
• Ileal disease:
  • Coeliac disease
  • Crohn’s disease
  • Tapeworm
  • Transcobalamin II deficiency
  • Resection
  • Blind loop syndrome
• Drugs:
  • Colchicine
  • Neomycin
  • Nitrous oxide (>12 hours)

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3. Pernicious (Addison’s) anemia

Megaloblastic anemia due to B12 malabsorption

Etiology:

• Autoimmune disease – Antibodies produced against gastric parietal cells (produce IF) and intrinsic factor, which is needed for B12 absorption

Clinical:

• Atrophic gastritis
• Achlorhydria

Diagnosis: Schilling test

Complications:

• Gastric cancer
• Peripheral paraesthesia

Management: hydroxocobalamin supplement

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4. Folate deficiency

Folate absorbed in small intestine

Etiology:

• Poor intake
• Poverty
• Old age
• Alcoholism
• Malabsorption:
  • Coeliac disease
  • Crohn’s disease
• Increased demand:
  • Infancy
  • Pregnancy
  • Chronic hemolysis
  • Malignant disease
  • Exfoliative skin
  • Chronic dialysis
• Drugs:
  • Alcohol
  • Barbiturates
  • Cotrimoxazole
  • Methotrexate
  • Primidone
  • Phenytoin
  • Pyrimethamine
  • Pentamidine
  • Triamterene
  • Oral contraceptives

Lab:

• Normal Schilling test – to rule out pernicious anemia
• Decreased folate levels in RBC
• Macrocytic cells

Complications: Neural tube defect + cleft lip-palate in fetus

Management: Folic acid supplements

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5. Aplastic anemia

Pancytopenia with non functioning bone marrow

Etiology:

• Genetic:
  • Fanconi anemia
  • Dyskeratosis congenita
• Autoimmune:
  • Graft vs host disease
  • Irradiation
• Drugs:
  • NSAIDS
  • Antithyroids
  • Allopurinol
  • Anticonvulsants
  • Sulphonamides
  • Chloramphenicol
  • Phenylbutazone
  • Penicillamine
• Virus: HIV, EBV, CMV, Hep B and C
• Chemicals:
  • Benzene
  • Toluene
• Heavy metals: Au, Pd, arsenic

Lab:

• TBC
• PBF
• Bone marrow aspirate

Management:

• Supportive: Antibiotics
• Definitive: Bone marrow transplant/stem cell transplant
• Hematopoietic growth factors
• Immunosuppressants
• Blood transfusion – risk infection and iron overload

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6. Hemolytic anemia

Hemoglobinopathy – Hereditary disorder, abnormal Hb production

• Thalassemia – Quantitative Hb defect – α/β
• Sickle cell – Qualitative Hb defect
  • Heterozygous (HbAS) – common
  • Homozygous (HbSS)
  • Heterozygous + another hemoglobinopathy

Sickle cell anemia

Etiology:

• In β chain of Hb, substitution of valine for glutamine
• In low oxygen/increased pH – RBC form sickle shape
• Low oxygen – HbS molecule polymerizes – gelation/crystallization – sickle shape forms

Clinical:

1. Anemia and hemolysis:
   • Jaundice
   • Gallstones
   • Reticulocytosis
   • Hyperbilirubinaemia
2. Crisis:
   • Hematological crisis
   • Dactylitis
   • Infarcts of vital organs – CNS stroke, multiorgan failure
   • Skin ulcers
   • Acute chest syndrome (fat emboli)
   • Recurrent pain
3. Impaired growth
4. Skeletal deformity
5. Susceptible to infections
6. Mild splenomegaly
7. Hypoxia

NB:

• Common cause of death – infections and thromboses
• Infarcts in jaw mimic tooth ache

Lab:

• TBC: Hb < 9g/dl
• PBF: Target cells and reticulocytes 5-25%, sickled erythrocytes
• Positive sickledex test
• Bone marrow – hyperplasia

X-Ray:

• Prominent cheek bones and skull changes (resemble crew cut) – Dues to bone resorption and 2ry bone formation

Management:

• Analgesics
• Antibiotics
• Blood transfusion only if CVS symptoms/ pulmonary thromboses
• Folate therapy
• Hydroxy urea – increased HbF

Dental management:

• HbAS:
  • In case of full GA – full oxygen maintained throughout
  • Treat respiratory infections vigourously
• HbSS:
  • AB prophylaxis for all procedures
  • Avoid elective surgery
  • Must have blood for transfusion, full anesthetic and emergency facilities

Thalassemia

Etiology:

• Mutations – decrease rate of synthesis of α or β globin chains
• Results in: Inadequate HbA and decreased MCHC
• Excess insoluble α globulin precipitates – membrane damage – further hemolysis

Clinical:

• Skeletal deformity – crew cut
• Splenomegaly, hepatomegaly
• Severe hemosiderosis
• Lymphadenopathy
• Growth retardation
• Cachexia

Lab:

• PBF:
  • Hypochromia RBC
  • Microcytic RBC
  • Marked poikilocytosis
  • Anisocytosis
  • Reticulocytosis
  • Normoblast (nucleated RBC)

• Bone marrow:
  • Erythroid hyperplasia
  • Increased medullary spaces
  • Infiltrates in cortex

X-ray: Cut crew appearance of skull + new bone formation

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7. Anemia as a complication of chronic disease

• Chronic inflammation
• Neoplasms
• Leukemia
• Liver disease
• HIV infection
• Rare – Hypothyroidism, hypopituitarism, hypoadrenocorticism, Uremia

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Platelets

Failed platelet production

• Congenital disorders: Type IIb Von Willebrand syndrome
• Megakaryocyte depression: Drugs, virus, chemicals
• General marrow failure:
  • Aplastic anemia
  • Leukemia
  • Megaloblastic anemia
  • Metastases
  • Drugs
  • Virus
  • Irradiation
  • Ethanol
  • Cytotoxics

Increased platelet destruction

• ITP
• HIV associated
• DIC
• SLE
• Chronic lymphocytic leukemia
• Malaria
• Drugs: ASA, B-lactam AB, valproate, cytotoxics
• Splenomegaly
• Transfusion of stored blood

Thrombocytopenia

Etiology: Commonly ITP – autoimmune disease

Clinical:

• Platelet < 100 x 109/L
• Petechiae, ecchymosis, post-op hemorrhage

Management:

• No LA if < 30 x 109/L
• Minor surgery if > 50 x 109/L
• Major surgery if > 75 x 109/L
• Correct with platelet rich plasma and platelet rich concentrate

Thrombocythaemia

Etiology:

• Myeloproliferative disease ± myelofibrosis/ polycythaemia/ chronic granulocytic leukemia

Clinical: Thrombosis due to increased platelets

Management:

• 32P – labelled phosphorus
• Plateletpheresis
• Interferon
• Corticosteroids
• ASA

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Acquired coagulation defects

1. Anticoagulant therapy

• Antagonize vitamin k activity – therefore prolonged prothrombin time and activated partial thromboplastin time
• Heparin (short term)
• Warfarin (long term)

2. Vitamin K deficiency

• Vitamin K synthesized in gut

Etiology:

• Broad spectrum AB for prolonged periods
• Poor absorption/ malabsorption
• Obstructive jaundice
• Failure of utilization
• Oral anticoagulant therapy
• Liver failure

Management:

• Vitamin K therapy (phytomenadiaone)

3. Liver disease

• Results in 2ry factor XII deficiency

4. Disseminated intravascular thrombosis (DIC)

Etiology:

• Incompatible blood transfusion
• Severe sepsis
• Obstetric complications
• Severe trauma
• Burns
• Cancer

Clinical:

• Hemorhagic tendencies
• Thrombotic phenomena
• Hemolysis
• Shock

Management:

• Correct underlying cause
• Treat hypoxia and acidosis
• Heparinization
• Replace clotting factors and platelets
• Antifibrinolytic therapy

5. DVT

Affects deep calf veins

Etiology:

• Immobility in elderly
• Bed ridden
• Post-op patients
• Oral contraceptives

Fatal complication: Pulmonary embolism

Prevention:

• Early mobilization
• Low dose SC heparin – 2 hours pre-op – then every 8-12 hours until patient on feet

Management: Low dose heparin