Dr. Radhwan Hazem Alkhashab discusses coagulation disorders and hemostasis. Normal hemostasis requires a balance between procoagulant and anticoagulant pathways. Coagulation studies are used to evaluate abnormal bleeding/thrombosis, assist with anticoagulation management, and help with massive transfusion resuscitation. The physiology of hemostasis involves platelets, vascular endothelium, and coagulation factors. Damage exposes tissue which activates platelets and coagulation pathways to form clots. Inherited bleeding disorders include von Willebrand disease and hemophilia A/B.

1. Coagulation disorders
Dr.Radhwan Hazem Alkhashab
Consultant anaesthesiologist & intensivist
2021

2. Introduction
Hemostasis comprises cellular and biochemical processes that limit blood loss
resulting from injury, maintain intravascular blood fluidity, and promote
revascularization of thrombosed vessels after injury.
Normal physiologic hemostasis necessitates a delicate balance between
procoagulant pathways responsible for generation of a stable localized
hemostatic "plug" and counter regulatory mechanisms inhibiting thrombus
formation beyond the injury site.
Vascular endothelium, platelets, and plasma coagulation proteins play equally
important roles in this process. Failure to maintain balance commonly leads to
excessive bleeding or pathologic thrombus formation.

3. Uses of coagulation studies
1) Evaluation of abnormal bleeding or thrombosis
2) Preoperative testing
3) Management of anticoagulation therapy
4) Assist in resuscitation management during massive transfusions.

4. Physiology of haemostasis
• The physiology of haemostasis involves a complex interaction
between the endothelium, clotting factors and platelets. Normally,
the subendothelial matrix and tissue factor are separated from
platelets and clotting factors by an intact endothelium. However,
when a blood vessel is damaged, vasospasm occurs, which reduces
initial bleeding and slows blood flow, increasing contact time
between the blood and the area of injury. Initial haemostasis occurs
through the action of platelets.

5. • Vascular endothelial injury, mechanical or biochemical, leads to
platelet deposition at the injury site, a process often referred to as
primary hemostasis, process mediated by activation of plasma
clotting factors and often referred to as secondary hemostasis
1. Primary hemostasis:
– Vascular spasm or vasoconstriction of the blood vessel,
– Platelet adhesion,
– Platelets activation (or secretion),
– Platelet aggregation.
2. Secondary hemostasis:
– Activation of clotting factors,
– Conversion of prothrombin to thrombin,
– Conversion of fibrinogen to fibrin

6. Vascular Endothelial Role in Hemostasis
Under normal conditions, vascular endothelium provides a non
thrombogenic surface to promote blood fluidity. Healthy endothelial
cells possess antiplatelet, anticoagulant, and profibrinolytic effects to
inhibit clot formation.
Damage to vascular endothelial cells expose the underlying
extracellular matrix (ECM) including collagen' von Willebrand factor
(vWF), and other platelet-adhesive glycoproteins. platelets bind to and
are activated by exposure to ECM components. Exposure of tissue
factor, constitutively expressed by fibroblasts in the ECM, activates
plasma-mediated coagulation pathways to generate thrombin and,
ultimately, fibrin clot.

7. Platelets and Hemostasis
Under normal circumstances platelets don't bind vascular
endothelium, however when injury exposes ECM platelet undergo
three major phases:
1.Adhesion
2.Activation.
3.Aggregations.
Exposure of subendothelial matrix proteins (i.e., collagen, vWF,
fibronectin) allows for platelet adhesion to the vascular wall.
As platelets adhere along the ECM, a series of physical and
biochemical changes occur termed platelet activation.

8. During the final phase of platelet aggregation, activators released
during the activation phase serve to recruit additional platelets to the
site of injury. Newly active glycoprotein receptors on the platelet
surface bind fibrinogen to provide for cross-linking with adjacent
platelets (platelet aggregation).

9. Plasma-Mediated Hemostasis
The coagulation cascade, might best be summarized as an
amplification system to accelerate thrombin generation from an inactive
precursor (i.e. prothrombin).
The ‘coagulation cascade“ describing plasma mediated hemostasis has
been depicted as intrinsic and extrinsic pathways, both of which
culminate in a common pathway where fibrin generation occurs.
Coagulation factors are, for the most part, synthesized hepatically and
circulate as inactive proteins termed zymogens

11. Extrinsic pathway. Clotting factors involved in the extrinsic
pathway include VII and III. The beginning of the process towards fibrin
clot formation is carried out by the extrinsic pathway, activated in
response to external tissue trauma, in which blood escapes from the
vascular system. Once the damage is identified, tissue factor (TF, or
III), a cell membrane protein, is released from the damaged cells. TF
binds with prothrombin (VII), activating it into VIIa, thereby initiating the
clotting cascade.
Intrinsic pathway. Clotting factors involved in this pathway include
XII, XI, IX, and VIII. The intrinsic pathway is activated by trauma that
begins inside the vascular system, prompted by internal damage to the
vessel wall. XII is activated into XIIa when it comes in contact with the
damaged endothelial collagen, thereby igniting the intrinsic pathway.

12. As the zymogen is converted to an active enzyme, a lower-case letter
"a“ is added to the Roman numeral identifier. For example, inactive
prothrombin is referred to as factor II, whereas active thrombin is
identified as factor IIa.
All coagulation factors, with the exception of factor VIII and von
Willebrand factor, are produced by the liver
Vascular endothelial cells synthesize factor VIII, levels of which are
therefore usually maintained in chronic liver disease. Vitamin
K is a necessary cofactor in the synthesis of prothrombin (factor II) and
factors VII, IX, and X.

14. • Both the intrinsic and extrinsic pathways result in a final common
pathway which involves the activation of factor X. Activated factor X
in turn converts prothrombin to thrombin (factor II to IIa), which
allows the conversion of fibrinogen to fibrin (factor I to Ia). Fibrin
then becomes cross-linked to form a clot.

16. There is a parallel system of anticoagulation, involving antithrombins
and proteins C and S, which help prevent an uncontrolled cascade of
thrombosis. Thrombin binds to thrombomodulin on the endothelium.
This prevents the procoagulant action of thrombin. In addition, the
thrombin–thrombomodulin complex activates protein C.
Factor Va increases the rate of conversion of prothrombin to thrombin
and factor VIIIa is a cofactor in the generation of activated factor X.
Inactivation of these two factors therefore leads to marked reduction in
thrombin production.

17. Antithrombin
Antithrombin is a serine protease inhibitor which is found in high
concentrations in plasma. It inhibits the action of activated factors VII,
X, XI, XII and thrombin. It is the site of action of heparin, which
increases its rate of action several thousand-fold.
In addition, platelet adhesion and aggregation are normally inhibited in
intact blood vessels by the negative charge present on the
endothelium, which prevents platelet adhesion, and by substances
which inhibit aggregation such as nitric oxide and prostacyclin.
Controlled fibrinolysis occurs naturally, involving the conversion of
plasminogen to plasmin, which in turn degrades fibrin. Plasminogen
can be activated by naturally occurring tissue plasminogen activator
and urokinase.

18. Common laboratory tests used to
investigate coagulation
1. The activated prothrombin time (PT): which tests for factors involved
in the extrinsic coagulation pathway (prothrombin, factors V, VII, X),
normal range 12–14 s, but often expressed as a ratio (the international
normalized ratio, INR)
2. The activated partial thromboplastin time (APTT): which tests for
factors present within the intrinsic pathway (including factors I, II, V,
VIII, IX and X), normal range 26–33.5 s, often also expressed as
a ratio (APTTR)
3. Thromoboplastin time (TT): which tests for the presence of
fibrinogen and the function of platelets, normal range 14–16 s
4. Fibrinogen level : normal range 200 and 400 mg/dL

19. Evaluation of Bleeding Disorders
A well-conducted history should focus on prior bleeding episodes
experienced by the patient.
Does the patient have a history of "excessive“ bleeding in association
with trauma or prior surgery? A history suggestive of a bleeding
disorder might include frequent epistaxis of a severity necessitating
"packing the nasal passage "or surgical intervention. Oral surgery and
dental extractions prove a particularly good test of hemostasis due to
high concentrations of fibrinolytic activity in the oral cavity Identification
of a bleeding disorder at an early age or in family members suggests
an inherited, as opposed to acquired, condition.

20. • A careful medication history including direct questions relating to
consumption of aspirin drugs, herbs, and fish oil may prove
noteworthy.
• Finally, inquiries regarding coexisting diseases should be included
(i.e., renal, hepatic, thyroid, bone marrow disorders, and malignancy)

21. Inherited Bleeding Disorders
Von Willebrand's disease:
Characterized by quantitative or qualitative deficiencies of vWF proves
the most common of inherited bleeding disorder.
Classically, patients with von Willebrand's disease describe a history of
easy bruising, recurrent epistaxis, and menorrhagia, all characteristic of
defects in primary (i.e., platelet mediated) hemostasis , In more severe
cases (i.e., type III vWD), concomitant reductions in factor VIII may lead
to serious spontaneous hemorrhage, including hemarthroses

22. Laboratory testing often demonstrates mild to moderate prolongation of
the activated partial thromboplastin time (aPTT), prolonged bleeding
time, decreased immuno reactive vWF concentrations.

23. Haemophilia
• Haemophilia can be classified as haemophilia A, B, or C depending
on the deficiency of the coagulation factors VIII, IX, or XI
respectively. Factors VIII and IX mainly play an important role in the
intrinsic pathway of the clotting cascade. These factors are required
for thrombin generation and fibrin formation.
• Classically, laboratory testing in patients with hemophilia reveals
prolongation of the aPTT, whereas the prothrombin time (PT) and
bleeding time remain within normal limits. Specific measurement
of factor VIII is used to diagnose the disease.

24. Anaesthetic considerations
1. A complete blood count, coagulation profile and fibrinogen level,
and specific factor assays must be done if indicated. All patients
must be evaluated for the presence of transfusion-related infections
such as HIV and hepatitis B and C.
2. Examination for the presence of joint deformities, contractures, and
a thorough airway assessment.
3. Perioperative avoidance of mucosal trauma, I.M. injections,
maintenance of normothermia, and pressure point care.
4. Care with vascular access and invasive monitoring. Consider early
use of ultrasound.
5. Risk–benefits for neuraxial block and regional blocks need to be
assessed individually and in general avoided.
6. Early mobilization, consider mechanical deep venous thrombosis
prophylaxis.

25. Sickle-Cell Disease
Sickle-cell disease is a genetic variation in the synthesis of haemoglobin
It involves a valine substitution in the β globin chain to make sickle
haemoglobin (HbS), and because it is an autosomal recessive condition,
individuals can either have HbA and HbS present (HbAS;
sickle-cell trait), or just HbS (HbSS; sickle-cell anaemia). HbS becomes
less soluble when deoxygenated, and aggregates, causing the red cell
to deform into the classic sickle shape which can lodge in the
microcirculation, becoming sequestrated and/or causing areas of
ischaemia.

26. Patients with sickle-cell disease are more likely to have preoperative
renal or splenic disease (in which case splenectomy prophylaxis may
be required).
They are also more likely to have suffered from lung disease, or
cardiovascular disease which may include previous cerebral infarctions.
• During anaesthesia, and during the postoperative period, HbS is
prone to sickling in the presence of hypoxemia, dehydration,
acidosis or mild hypothermia. In patients with HbSS, sickling may
occur even at high oxygen saturations and become progressively
worse, such that all red cells will be sickled at approximately 50%
saturation. If sickling causes lung ischemia, further hypoxaemia may
develop.

27. • Intraoperative anaesthetic techniques should avoid hypoxaemia and
acidosis, and this may involve general or regional anaesthesia. If
general anaesthesia is required, intermittent positive pressure
ventilation may be preferable as a means of optimizing oxygenation
and avoiding respiratory acidosis.
• Intravenous fluids (including in the preoperative period) and active
warming of the patient are likely to be required to avoid dehydration
and hypothermia. Vasopressors and limb tourniquets should be
used with caution to avoid triggering of sickling.
• Anaesthetists may also be called upon to provide analgesia,
including patient-controlled morphine, to patients suffering from a
non-surgical sickle-cell crisis. These are often extremely painful.

28. Thalassemia
Thalassaemia is an abnormality of globin synthesis , There are two
common forms, alpha and beta, and both forms are inherited in a
recessive pattern and can thus be present in minor or major forms.

29. • In the major forms, haemolytic anaemia occurs, which is often
managed with regular blood transfusions in order to prevent
anaemia and bony deformation caused by bone marrow
hyperplasia. In untreated individuals, marrow hyperplasia can result
in craniofacial abnormalities, which may directly affect anaesthetic
techniques such as laryngoscopy.
• Iron overload resulting in cardiac hypertrophy, pulmonary
hypertension and liver disease; detailed cardiac history and
preoperative assessment are required.
• Various drugs are relatively contraindicated in thalassaemia
because they may trigger haemolysis; these include prilocaine,
nitroprusside, penicillin, aspirin and vitamin K.

30. Acquired bleeding disorders
• Heparin, warfarin, and fibrinolytic drugs accounted for most serious
drug-induced bleeding complications.
• Heparin derives its anticoagulant effect by interacting with plasma
antithrombin . The half-life of heparin is 1 to 2 hours and varies
directly with total dose. Heparin is cleared from the circulation
both renaly and hepatically. Most often, heparin's anticoagulant
effect is monitored using the aPTT with a target prolongation of one
and one-half to two times control, commonly used for treatment of
venous thrombosis.

31. • At heparin concentrations exceeding measurement limits of the
aPTT such as during cardiopulmonary by pass or interventional
cardiovascular procedures, the activated clotting time (ACT)
provides an alternative albeit less sensitive, measure of heparin
anticoagulation. Heparin's anticoagulant effect is rapidly reversible
by protamine administration.

32. Conditions Which are Known to Increase
Blood Loss
I. Coagulopathy 1.Anticoagulant drugs
2. Autoimmune dis.
3.Congenital dis. Hemophilia A,B
Von W. dis.
4.DIC
5.Hemodilution Massive blood
transfusion
6.Liver dis.
7. Vit. K deficiency Biliary tract disorders
Inadequate diet
8.Envenomation Snake venom
(hypofibrinogen,DIC,,
platelet antagonism)

33. Conditions Which are Known to Increase
Blood Loss
II. Platelet disorders 1. Decrease production: Aplastic anemia
Folate deficiency
Liver dis.
Malignancy (BM infiltration)
Viral infection (HIV)
Vit. B12 deficincy
2. Increase consumption: Auto ITP
DIC
Drugs (heparin)
HELLP syndrome
Hypersplenism
Sepsis
Infections (HIV)
3.Impaired function: Uremia
Hypergammaglobinemia

34. Conditions Which are Known to Increase
Blood Loss
III. Vascular disorders 1.Acquired Henoch –schonlen purpura
Vitamin C deficiency
2.Congenital Hereditary hemorrhagic telangiectasia
Ehlers danlos syndrome
Intramuscular injections are not recommended in coagulopathic patients
because of the risk of intramuscular haemorrhage, and the use of NSAIDs
may exacerbate the bleeding tendency.

35. Coagulopathy Of Trauma
• Patients who have suffered major trauma have a high incidence of
coagulopathy.

36. Factors Associated with Coagulopathy in
Trauma
1. Physiological dilution of clotting factors
2. Hypothermia
3. Acidosis
4. Red cell loss
5. Trauma-induced fibrinolysis
6. Injury-related inflammation
7. Hypoperfusion
8. Hypocalcaemia.
9. Iatrogenic – dilution by fluids, anticoagulant effects of intravenous
fluids

37. Disseminated Intravascular Coagulation
(DIC)
• Disseminated intravascular coagulation (DIC) is characterized by
systemic activation of blood coagulation, which results in generation
and deposition of fibrin, leading to microvascular thrombi in various
organs and contributing to multiple organ dysfunction syndrome
(MODS).Consumption of clotting factors and platelets in DIC can
result in life-threatening hemorrhage.
Derangement of the fibrinolytic system further contributes to
intravascular clot formation, but in some cases, accelerated
fibrinolysis may cause severe bleeding. Hence, a patient with DIC
can present with a simultaneously occurring thrombotic and
bleeding problem, which obviously complicates the proper
treatment.

38. Clinical conditions associated with DIC
1. Sepsis and severe infection ,(including COVID-19 )
2. Trauma (neurotrauma)
3. Organ destruction (e.g., pancreatitis)
4. Malignancy.
5. Severe transfusion reactions
6. Obstetric: Amniotic fluid embolism,(HELLP) syndrome; eclampsia.
7. Retained dead fetus syndrome
8. Vascular abnormalities.
9. Severe hepatic failure.
10. Heat stroke and hyperthermia

39. Diagnostic Scoring System for Disseminated
Intravascular Coagulation (DIC)
Scoring:
• If > 5 compatable
with DIC
• If < 5 suggestion
of DIC

40. Complications of DIC
i. Acute kidney injury
ii. Change in mental status
iii. Respiratory dysfunction
iv. Hepatic dysfunction
v. Life-threatening thrombosis and hemorrhage (in patients with
moderately severe–to–severe DIC)
vi. Cardiac tamponade
vii. Hemothorax
viii. Intracerebral hematoma
ix. Gangrene and loss of digits
x. Shock
xi. Death

41. Circulatory signs include the following:
• Signs of spontaneous and life-threatening hemorrhage
• Signs of subacute bleeding
• Signs of diffuse or localized thrombosis
• Bleeding into serous cavities
Central nervous system signs include the following:
• Nonspecific altered consciousness or stupor
• Transient focal neurologic deficits.

42. Cardiovascular signs include the following:
• Hypotension
• Tachycardia
• Circulatory collapse
Respiratory signs include the following:
• Pleural friction rub
• Signs of acute respiratory distress syndrome (ARDS)
Gastrointestinal signs include the following:
• Hematemesis.

43. Genitourinary signs include the following:
• Signs of azotemia and renal failure
• Acidosis
• Hematuria
• Oliguria
• Uterine hemorrhage
Dermatologic signs include the following:
• Petechiae
• Jaundice (liver dysfunction or hemolysis)
• Purpura
• Hemorrhagic bullae
• Skin necrosis of lower limbs (purpura fulminans)
• Localized infarction and gangrene
• Wound bleeding and deep subcutaneous hematomas
• Thrombosis

44. Standard tests for DIC
In clinical practice, a diagnosis of DIC can often be made by a
combination of the following tests .
• Platelet count: Thrombocytopenia is seen in as many as 98% of DIC
patients, and the platelet count can dip below 50 × 109/L in 50%
• Global clotting times (aPTT and PT):are typically prolonged may
reflect the consumption and depletion of various coagulation factors.
Protein C and antithrombin are natural anticoagulants that are
frequently decreased
• One or two clotting factors and inhibitors (eg, antithrombin):
The massive fibrin deposition in DIC suggests that fibrinogen levels
would be decreased.
• Assay for D-dimer or FDPs:D-dimer elevation means that thrombin
has proteolyzed fibrinogen to form fibrin that has been cross-linked
by thrombin-activated factor XIIIa.

45. Management of the DC
Management of the DC itself has the following basic features:
1. Monitor vital signs
2. Assess and document the extent of hemorrhage and thrombosis
3. Correct hypovolemia
4. Administer basic hemostatic procedures when indicated.

46. • Heparin should be provided to those patients who demonstrate
extensive fibrin deposition without evidence of substantial
hemorrhage
• In general, antifibrinolytic agents (eg, tranexamic acid, ε-
aminocaproic acid) should be avoided in DIC because they are
known to produce thrombotic complications, such as myocardial
infarction and renal artery thrombosis when there is systemic
clotting. However, in patients with trauma and massive blood loss,
tranexamic acid has been shown to be effective in reducing blood
loss and improving survival

47. Administration of Blood Components
and Coagulation Factors
• Platelet and coagulation factor replacement should not be instituted
on the basis of laboratory results alone; such therapy is indicated
only in patients with active bleeding and in those requiring an
invasive procedure or who are otherwise at risk for bleeding
complications.
1. Platelets
• Platelet transfusion may be considered in patients with DIC and
severe thrombocytopenia, in particular, in patients with bleeding or
in patients at risk for bleeding. In actively bleeding patients, platelet
levels from 20 × 109/L to 50 × 109/L are grounds for platelet
transfusion (1 or 2 U/kg/day).

48. 2. Coagulation factors
• Specific deficiencies in coagulation factors, such as fibrinogen, can
be corrected by administration of cryoprecipitate or purified
fibrinogen concentrate in conjunction with fresh frozen plasma (FFP)
administration.

49. Anticoagulation
Heparin can at least partly inhibit the activation of coagulation in cases
of sepsis and other causes of DIC. Moreover, antithrombin, the primary
target of heparin activity, is markedly decreased in DIC, which means
that the effectiveness of heparin therapy will be limited without
concomitant replacement of antithrombin.

50. Heparin-Induced Thrombocytopenia
• Two distinct types of HIT can occur: nonimmune and immune-
mediated. Nonimmune HIT, which occurs most frequently, is
characterized by a mild decrease in the platelet count and is not
harmful. The second type, immune-mediated HIT, occurs much less
frequently but is dangerous. Immune-mediated HIT causes much
lower platelet counts. Paradoxically, despite a very low platelet
count, patients who suffer from HIT are at risk for major clotting
problems.
• Immune-mediated HIT usually occurs between 5 to 14 days after
first beginning heparin therapy.

51. How Is HIT Diagnosed?
HIT can often be diagnosed by
measuring the platelet count and
PF4 antibody level in the blood.
Symptoms of new blood clot
formation may suggest HIT.

52. How Is HIT Treated?
The first step is to discontinue
heparin on suspicion of HIT. The
next step is to treat HIT using an
alternative type of anticoagulant.
Even though the platelet count is
low, it is important to avoid
platelet transfusions, which can
“add fuel to the fire.”
Common drugs use to treat HIT

53. Interventional procedures & regional anaesthesia in
coagulopathy patients
Interventional procedures such as the insertion of central venous
catheters, epidural block or regional nerve blocks constitute a
significant risk in coagulopathic patients in terms of hemorrhage or
haematoma formation. Of particular note are the risks of airway
obstruction from failed jugular venous catheter insertion, and paralysis
caused by epidural hematoma formation.
INR of ≤ 1.4 have been considered relatively safe for most procedures
undertaken by anesthetists.

54. • LMWH (thromboprophylaxis dose): needle insertion should be
delayed until 12 h after last dose; epidural catheters should be
removed at least 12 h after the last dose and at least 4 h before the
next dose
• Subcutaneous unfractionated heparin thromboprophylaxis: needle
insertion should be delayed until 4 h after the last dose; epidural
catheters should be removed at least 1 h before the next dose
• NSAID therapy, including low-dose aspirin, can be continued and
does not seem to represent an increased risk