Haemorrhage and Blood Transfusion - Exam Notes

1. HAEMORRHAGE

Classification

• Primary: Occurs at time of injury/operation
• Reactionary: Within 24 hours (commonly 4-6 hours)
  • Precipitating factors: Coughing, vomiting, straining, rise in BP, restlessness, venous refilling during recovery from anaesthesia, slipping of ligature, clot dislodgement
  • Common causes: Thyroid surgery, cholecystectomy, major abdominal surgeries, circumcision, hydrocele surgery, tonsillectomy
• Secondary: Usually 1-14 days after surgery
  • Factors: Infection, pressure by drain/bone, malignancy
  • Common causes: Erosion of carotid artery by cancer (secondaries in neck), haemorrhoidectomy, inguinal block dissection

• Acute haemorrhage: Sudden, severe - after trauma/surgery
• Chronic haemorrhage: Repeated bleeding over long period (haemorrhoids, bleeding peptic ulcer, carcinoma caecum) - presents with chronic anaemia + hyperdynamic cardiac failure; in transitional state of chronic hypovolaemia; corrected by packed cell transfusion
• Acute on chronic: Most dangerous - individual already hypoxic, worsens faster

• Surgical haemorrhage: Corrected by surgical intervention
• Non-surgical haemorrhage: Diffuse ooze due to coagulation abnormalities and DIC

Pathophysiology of Haemorrhage

Trauma-Induced Coagulopathy (TIC)

• Clinical syndrome caused by imbalance between clotting, anticoagulation and fibrinolysis
• Results from multiple pathological factors: haemorrhage + tissue injury in early trauma
• Closely related to outcome of trauma patients

• Early endogenous process, driven by combination of tissue injury + shock
• Associated with increased mortality in polytrauma patients
• 25% of TIC patients develop ATC within minutes of trauma
• Endogenous coagulopathy syndrome with bleeding from non-surgical sites (mucosa, serosa) with hypothermia, acidosis, haemodilution

• Injury Severity Score (ISS) > 25
• Systolic BP < 70 mmHg
• Acidosis with pH < 7.10
• Hypothermia with body temperature < 34°C

1. Hypothermia (temp < 36°C) - clotting factor and platelet function severely reduced
2. Metabolic acidosis
3. Progressive coagulopathy - coagulation affected when factors below 25%

• Fibrinogen level < 1.5 to 2 g/L + platelet < 50,000/cumm = increased risk of bleeding tendency

Note: Normal lactic acid = 0.5-1 mmol/L; hyperlactatemia = raised lactic acid level between 2-4 mmol/L without metabolic acidosis; lactic acidosis = lactate > 4 mmol/L with metabolic acidosis

Clinical Features of Haemorrhage

• Pallor, thirsty, tachycardia, nausea, air hunger
• Cold clammy skin due to vasoconstriction (pale appearance)
• Tachycardia, dry mouth, oliguria
• Rapid thready pulse, specific focused causes
• Cardiac depression: Hypoxia, liver effect; dysfunction
• GI effect: Hypertonic ileostomy discharge, AV-M
• Lung: MODS - ARDS

• BP < 100 mmHg
• Pulse > 100/minute; systolic > 10 mmHg
• Diastolic BP drop on sitting or standing
• Shock index (pulse rate : blood pressure ratio) > 1 (cardiac index)

Note: Tachycardia is NOT a reliable indicator of haemorrhage

Classification of Haemorrhagic Shock

Measurement of Blood Loss

• Blood loss in closed tibial fracture = 500 mL; femur fracture = 500-2,000 mL
• Weighing swabs before and after use is important on-table method
• Rains factor = Total difference in swab weight × 1.5
• Total blood loss = Total difference in swab weight × 2 (for larger wounds/operations)
• Hb% and PCV estimation
• Blood volume estimation using radioiodine technique or micro haematocrit method
• Measurement of CVP or PCWP
• Specific investigations: U/S abdomen, Doppler, angiogram in vascular injury, chest X-ray in haemothorax, CT scan in major injuries, CT scan head in head injuries

Treatment of Haemorrhage

• Airway, Breathing, Circulation - Oxygen 15 L/minute
• Correction of hypotension by fluid therapy
• Two wide bore IV cannulae inserted; blood drawn for grouping, cross-matching, and essential investigations
• Warm normal saline or Ringer lactate until blood is ready

Important: Crystalloids cause dilutional coagulopathy without oxygen carrying capacity; also cause hyperchloraemic acidosis. Unwarmed fluid causes hypothermia. Isotonic, hypotonic and colloid solutions leak into interstitial space. Haemaccel, SAG-M blood and dextran can be used initially.

• Sites: Upper end of tibia (preferred in children), lower end of femur/radius, manubrium sterni, iliac crest
• Technique: Bone held firmly under LA, needle perpendicular with rotational movement; loss of resistance confirms bone marrow entry; connected to IV fluids; free flow confirms entry
• Can be kept for 48 hours
• Complications: Osteomyelitis, extravasation, cellulitis, compartment syndrome, fracture (in children)

• Pressure, Packing, Position, Rest (to stop blood ooze)

• Wound exploration + ligation of small vessel
• Suturing the wound/vessel (anastomosis)
• Topical applications: Oxycel, gauze soaked with adrenaline, bone wax for bone ooze, collagen, thrombin

• Elevation, ligation, suturing of venous wall, pressure bandaging, packing

• Packing; intra-abdominal packing for retroperitoneal or intra-abdominal haemorrhage (DAMAGE CONTROL SURGERY)
• CT, DPL, body ultrasound, Doppler
• Therapeutic embolisation
• Upper/lower GI bleeding - endoscopic or angiographic control

• Earlier and more aggressive correction of coagulopathy and metabolic derangement with permissive hypotension
• Use blood products over isotonic fluid for volume replacement
• Rapid and early correction of coagulopathy with component therapy

• Oxygenation, intubation/ventilation
• Head down (Trendelenburg) position, monitoring
• Absolute rest, analgesics; morphine 10-20 mg IM/IV
• Tourniquet is often used but is NOT advisable as a first aid measure
• TPN, CVP monitoring, electrolyte management
• Steroid injection, antibiotics, ventilator support
• Treat acidosis, hypothermia, hypocalcaemia and coagulopathy

• Haemostasis (pressure, packing)
• Exposure (of bleeding area by proper dissection)
• Localize (the bleeding point specifically and accurately)
• Precisely act to control bleeding (bipolar/clips/suture/glue)
• Call for HELP

End-Points of Resuscitation

• Keep patient warm (prevention of hypothermia; temperature below 32°C is lethal)
• Warn: if the package has been opened, the sterility of the product cannot be guaranteed
• Correction and prevention of further coagulopathy (TIC)
• Fibrinogen infusion (TEG) and initial rotation thromboelastometry (ROTEM) assessment
• Tranexamic acid: 15 mg/kg initial infusion, then 5 mg/kg per hour
• Fibrinogen and prothrombin complex concentrate (PCC) transfusion avoids packed cell and platelet transfusions
• Cryoprecipitate and recombinant activated factors also significantly beneficial
• Fluid and electrolyte management, sepsis control (antibiotics)
• Further monitoring: hourly urine output, haemodynamic stability, respiration, lactic acid, base deficit, fibrinogen, platelet, prothrombin INR, APTT, haematocrit, ABG, liver and renal functions
• Blood transfusion required if Hb% is < 8 g/dL (raise 1%)

1. Confirm shock, hypovolaemia and haemorrhage by clinical assessment
2. Identify cause of haemorrhage - DPL, body ultrasound, CT, DPL, body scopy
3. Damage control - stop blood loss
4. Definitive treatment if any
5. Sepsis control
6. Prevention of coagulopathy by FFP, platelet concentrate, fresh blood
7. Critical care management
8. End point resuscitation, fluid and electrolyte management, prevention of organ failure

Local Haemostatic Agents

2. BLOOD TRANSFUSION

Indications

• Acute blood loss following trauma ≥ 15% of total body volume in otherwise healthy individuals (liver, spleen, kidney, GIT injuries, fractures, haemothorax, perineal injuries)
• During major surgeries: abdominoperineal surgery, thoracic surgery, hepatobiliary surgery
• Following burns; in septicaemia
• As a prophylactic measure prior to surgery
• Whole blood - given in acute blood loss
• Packed cells - given in chronic anaemia
• Blood fractions - given in ITP, haemophilias

Donor Criteria

• Donor should be fit without any serious diseases: HIV1, HIV2, hepatitis, malaria
• Weight of donor > 45 kg

Collection and Storage of Blood

• Collected in a sac containing 75 mL of CPD (Citrate Phosphate Dextrose) solution; stored in special refrigerators at 4°C
• CPD blood storage life = 3 weeks
• Adding adenosine increases storage life to 5 weeks = CPDA solution

• Currently used; storage life = 5 weeks at 2-6°C
• Good viability of cells; very useful in anaemias
• Devoid of any proteins
• Precautions: For every 4 units of SAG-M, 1 whole blood must be given. Later for every 2 units SAG-M, 1 unit (400 mL) of 4.5% human albumin must be given. Check coagulation and platelet count regularly.

• RBCs last 3 weeks
• WBCs destroyed rapidly
• Platelets reduced in 24 hours; last only 2.5 days
• Clotting factors labile - levels fall quickly in 1-2 days
• Blood should be destroyed in 7 days if RBC laden are beyond 7 days

Blood Transfusion Procedure

• After grouping and cross-matching, 540 mL of blood is transfused in 4 hours (40 drops/minute) using a filtered drip set
• 1 mg of iron per day; iron overload occurs after 350 mg of iron transfused
• Normal transfusions: Iron excretion 1 mg/day; iron overload can occur
• Iron excretion can be increased by desferrioxamine infusion

Blood Fractions

• Fresh plasma rapidly frozen; stored at -40°C
• Contains all coagulant factors (but only 3%)
• Can be stored for 2 years
• Uses:
  • Severe liver disease with abnormal coagulation
  • Deficiency of clotting factors following warfarin therapy, DIC, massive transfusion
  • To maintain prothrombin time at normal level
• Dose: 15 mL/kg

• Obtained by centrifuging whole blood at 2000-2300 g for 15-20 minutes
• Volume = 200 mL with haematocrit ~70%; one unit increases Hb by 1%
• Indicated in chronic anaemia, preoperative (35 days or 1-6°C, children up to 7 days)
• Not indicated for cardiac overloading; old age; in patients with cardiac problems

• When FFP is allowed to thaw at 4°C, visible white supernatant layer develops = cryoprecipitate
• Rich in Factor VIII and fibrinogen
• Stored at -40°C; can be kept for years
• Used to raise fibrinogen level; also contains Factor XIII, von Willebrand factor
• Dose: 0.1 unit/kg; dose to raise fibrinogen = 15 mL/kg; to keep plasma level will be administered in DIC
• Risk: Fever, urticaria, allergic reactions; rarely transmitted infections

• Used in haemophilia A and von Willebrand disease
• Freeze-dried, purified human coagulation Factor VIII (Virus inactivated)
• Risk: same as FFP; historically risk of HIV, hepatitis

• Used in haemophilia B
• Freeze-dried; used in orthopaedic/amputation/mandibular resection/dental surgeries
• Complications: allergic reactions, thromboembolism; risk of hepatitis/HIV; microaggregates; fat embolism; cost; cross-reaction with non-vascular vessels

• Contains 1.0 mg with haematocrit ~30%; in 200 mL of plasma
• One single donor platelet is obtained by centrifugation
• Indicated in burns, hypoalbuminaemia, severe thrombocytopaenia, drug (aspirin, clopidogrel) induced haemorrhage
• Dose: 0.1 unit/kg; transfused when platelet drops below 20,000 or episodes of bleeding
• 1 platelet concentrate increases up to 10,000 platelet/cumm in one hour
• Stored at 4°C: use within 48 hours; at room temperature: use up to 5 days

• Prepared by platelet pheresis on a donor
• Contains 3 × 10^11 platelets in 200 mL of plasma
• Equivalent to 6-8 units of random donor platelet

• Derived from plasma which contains factors II, IX and X; used in uncontrolled haemorrhage where there is deficiency of these factors
• Uses: Severe liver disease, deficiency following warfarin therapy, DIC, massive transfusion

• Used in 4-5 different fragments
• Obtained after repeated fractionation and can be stored for several months in liquid form at 4°C
• Used in burns, hypoalbuminaemia, nephrotic syndrome, ovarian hyperstimulation syndrome (occurring after ovarian stimulation with gonadotrophin injections during IVF therapy)
• 1 gram of albumin binds with 14 mL of water (increases blood volume)
• Used daily as needed until good response; albumin is expensive

Plasma Expanders

• Polysaccharides of varying molecular weights; derived from Leuconostoc mesenteroides bacteria after adding yeast
• 1 gram of dextran binds with 20 mL of water
• Precautions: Take blood sample for grouping/cross-matching BEFORE giving dextrans (interferes with rouleaux formation); also interferes with platelet function; total volume must NOT exceed 1,000 mL; can cause hyperchloraemic acidosis and central pontine myelinolysis
• Dextran 40 (Low MW 40,000): Very effective in restoring blood volume immediately; small molecules readily excreted - effect transitory; useful in prevention of sludging in kidney
• Dextran 70/110 (High MW): Less effective but long-acting; useful for prolonged effect

• Degraded form, MW 30,000
• 1,000 mL of 3.4-4% solution given IV
• Less effective than dextran; after 4 hours only 30% remains intravascular

• Contains starch, sodium hydroxide, ethylene oxide
• Good plasma volume expander but lasts only 6 hours

Complications of Blood Transfusion

1. Congestive cardiac failure - circulatory overload in patients with CCF receiving repeated blood transfusions
2. Transfusion reactions:
   • Incompatibility: Major and minor reactions with fever, rigors, pain, hypotension
   • Acute haemolytic transfusion reaction (AHTR): ABO incompatibility; most dangerous (90%+ mortality); haemolysis, haemoglobinuria, fever with chills, tachycardia, hypotension, cardiac arrest - STOP transfusion immediately; give dexamethasone IV immediately; fluid therapy, alkalization of urine
   • Pyrexial reactions due to pyrogenic ingredients
   • Allergic reaction (3%): Urticaria and allergy to specific proteins in donor plasma; mild - treated with steroid and antihistaminics; in severe urticaria - that unit of blood discarded; new washed RBCs and platelets used
   • Sensitisation to leucocytes and platelets
3. Immunological sensitisation
4. Infections: Serum hepatitis (HBV, HCV), HIV, bacterial infection, malaria, Epstein-Barr virus, CMV, syphilis, Yersinia, Babesia microti, Trypanosoma cruzi
5. Air embolism, Thrombophlebitis
6. Coagulation failure - dilution of clotting factors, DIC, dilutional thrombocytopenia (occurs in massive blood transfusion)
7. Circulatory overload causing cardiac failure
8. Haemochromatosis in patients with CRF receiving repeated blood transfusions
9. Citrate intoxication - bradycardia and hypocalcaemia; for every 4 units of blood, 10 mL of 10% calcium chloride or calcium gluconate should be infused IV
10. Iron overload - 1 mg/day; overload after 350 mg iron
11. Graft-versus-host disease (GVHD): Rare; transfusion-related; reaction of tissues by lymphocytes in stored blood in recipient; common in immunosuppressed; reduced blood can be irradiated to 90%+ toxicity level to prevent; quantitative cardiac failure if several allergic transfused units; often goes unnoticed
12. Acute Respiratory Distress Syndrome (ARDS), DIC, Congestive Cardiac Failure (CCF)

Note: Autologous blood transfusion - where > 30% is transfused, patient's own blood should be used; allow at least 2 weeks prior to surgery if possible; patient's blood is meticulously sucked out and then filtered and reused through a stem cell system

Massive Blood Transfusion

• Hypothermia
• Coagulation failure
• Citrate intoxication (hypocalcaemia)
• Iron overload
• DIC
• ARDS

Erythropoietin

• Used in CRF patients who are on haemodialysis; increases the RBC count
• Given 1,000-3,500 units twice weekly; costly
• Used to reduce the number of transfusions

3. ARTIFICIAL BLOOD

Red Cell Substitutes

• Abiotic RBC substitute; synthetic oxygen carrier
• Half-life = 7 days with high affinity for O2
• Inert, colourless, odourless, dense, poorly soluble, biocompatible liquid
• Must be emulsified with albumin or lipids before infusion (emulsion alone injection can cause pulmonary embolism)
• Can bind and release oxygen
• 1.3 mL of oxygen/100 mL released; should be kept frozen
• Disadvantage: Patient has to breathe hyperO2 PPO2 quickly; patient has to be emulsified
• Can cause anaphylaxis

• More affinity for oxygen as it does not contain 2,3-DPG
• Short half-life; nephrotoxic

• On-table blood is collected, washed, filtered and transfused
• Used in major trauma

• Stored at 4°C; stable for long periods
• Used in cirrhosis, burns, nephrotic syndrome, ovarian hyperstimulation syndrome
• 1 gram binds with 14 mL of water

4. TOURNIQUETS

Types

Uses

• Bloodless field in limb surgeries (upper/lower limb, orthopaedic, soft tissue tumours, amputations)
• IV injections and IV sampling (rubber tourniquet)
• Diagnostic tests for varicose veins, purpura (ITP), carpal tunnel syndrome, tetany
• First aid in bleeding conditions of limbs, snake bite (controversial)
• Small procedures in fingers and toes

Application Rules

• Upper limb: Applied at mid-thigh level; pressure = 150-250 mmHg
• Lower limb: Pressure = 300 mmHg (in children, lower pressure)
• NOT applied over the forearm or leg; applied below the elbow above the joint
• Applied over layers of gauze or cotton, NOT over bare skin
• Must not be applied closer to joints
• Time limit: Upper limb = 1 hour; lower limb = 2 hours; can be re-applied with interval

Contraindications

• Peripheral vascular disease and atherosclerosis
• Infection; deep venous thrombosis
• Crush injuries; sickle cell disease

Complications

• Tourniquet palsy - Neuropraxia; in upper limb = radial nerve involvement; leads to more bleeding; improperly applied tourniquet in high thigh = crush to sciatic nerve
• Skin blistering
• Infection
• Necrosis of tourniquet in finger/toe if tourniquet is used in fingers/toes

5. DISSEMINATED INTRAVASCULAR COAGULATION (DIC)

Causes

• Major trauma - release of tissue thromboplastin
• Burns (most common cause of DIC)
• Major surgery, common
• Obstetric causes: Septic abortion, abruption, retained dead foetus, amniotic fluid embolism
• Septicaemia: Meningococcal, malarial, gram-negative septicaemia
• Vascular diseases: Acute pancreatitis, placenta praevia, releasing proteolytic enzymes
• Malignancy: Carcinoma of pancreas, prostate, acute promyelocytic leukaemia
• Haemolysis: Snake bite, liver dysfunction

Types

• Acute DIC: Presents with bleeding in gums, GIT, venipuncture site, haematuria, petechiae, oozing from surgical or traumatic wounds; massive bleeding also can occur
• Chronic DIC: Low-grade type with thrombotic features

Investigations

• Platelet count - reduced
• Thrombin time (TT), prothrombin time (PT) and APTT - all prolonged
• Fibrinogen degradation products (FDP), D-dimer test - raised
• Complete haematocrit, renal function tests, LFT, electrolyte estimation, blood/discharge/pus/urine culture

Treatment

1. Treatment of specific cause as per protocol
2. Correction of haemodynamic instability by fluid therapy, transfusion (packed cells or whole blood), dopamine/dobutamine therapy
3. Factor replacement:
   • FFP at 15 mL/kg
   • Cryoprecipitate to raise fibrinogen level; 0.1 unit/kg; platelet drops to set below 20,000 or with episodes of bleeding
   • Platelet transfusion at dose 0.1 unit/kg when platelet is below 20,000
4. Heparin: Controversial; mainly used in chronic DIC, DIC with purpura, DIC of obstetric cause, cancer-induced DIC, DIC due to acute antiphospholipid antibody syndrome
5. EACA, tranexamic acid - used but with questionable benefits

6. MECHANISM OF BLOOD COAGULATION (HAEMOSTASIS)

Process of Haemostasis

1. Platelet adhesion to injured vessel/capillary wall
2. Activated platelets release ADP (adenosine diphosphate) → more platelet aggregation
3. Activated platelets release Thromboxane A2 → further increases adhesion and aggregation
4. Circulating fibrinogen binds to activated platelet receptors glycoprotein IIb and IIIa
5. This activates the coagulation system → factor Xa → prothrombin → thrombin → converts soluble fibrinogen to insoluble fibrin
6. Clotting factors II, VII, IX and X are vitamin K dependent; synthesised in liver (carboxylation of glutamic acid residues); factor targets coagulates activation to enzyme by partial proteolysis which in turn activates other needed double coagulation factors and activates converts prothrombin and fibrinogen, eventually converting soluble fibrinogen to insoluble fibrin

Coagulation Cascade

• Prekallikrein, kininogen → Factor XII → XIIa
• XI → XIa
• IX → IXa (with Factor VIII, platelet factor)
• X → Xa

• VI, II (Tissue phospholipid) → VII → VIIa
• X → Xa

• Factor Xa + V, Ca2+, platelet factor → Prothrombin → Thrombin (IIa)
• Fibrinogen (I) → Fibrin soluble (Ia) → with XIIIa → Fibrin insoluble

Note: In vitro coagulation occurs by intrinsic coagulation system

Blood Clotting Factors Table

7. HAEMOPHILIA AND VON WILLEBRAND DISEASE

Haemophilia A (Classic Haemophilia)

• Cause: Deficiency of Factor VIII C
• Genetics: X-linked recessive trait - occurs in males and homozygous females
• Factor VIII has two components:
  • Smaller component - Factor VIII C: Needed for activation of Factor X in intrinsic coagulation pathway; its deficiency = classic haemophilia
  • Larger component - von Willebrand Factor (vWF): Facilitates adhesion of platelets to subendothelial collagen; essential for haemostasis
• Features:
  • Recurrent haemarthroses (common)
  • Petechiae and ecchymoses are ABSENT
  • Bleeding time = NORMAL
  • Coagulation time = PROLONGED
• Treatment: Replacement of Factor VIII; if not known, patient may have life-threatening bleeding even after dental extraction

Von Willebrand Disease

• Cause: Deficiency of larger component (99%) of Factor VIII - vWF
• Genetics: Autosomal dominant
• Features:
  • Normal bleeding time; normal platelet count
  • Spontaneous bleeding from mucous membrane
  • Excessive bleeding from wounds
  • Severe menorrhagia
  • Haemarthroses is NOT COMMON (differs from Haemophilia A)
• Treatment: Replacement of specific factors (vWF)

Haemophilia B (Christmas Disease)

• Cause: Deficiency of Factor IX
• Genetics: X-linked autosomal recessive trait
• Treatment: Factor IX replacement