2. OBJECTIVES
• Define hematopoiesis
• Explain the types of stem cells
• Explain the process of hematopoiesis- Primitive &
definitive wave
• List the sites of hematopoiesis
• List & explain the various hematologic conditions seen
in the ICU
• Other hematologic disorders- Plasma cell dyscrasias
• Define coagulation & hemostasis
• Explain the types of hemostasis- Primary & secondary
• Explain the coagulation physiology
3. Cont….
• Coagulation cascade- Intrinsic, Extrinsic & Common
Pathways
• List the various coagulation factors & related
substances
• Explain about monitoring of blood coagulation-
coagulation profile (Bleeding time, PT/INR, PTT/aPTT,
TCT & Fibrinogen assay)
• List & explain the various coagulation disorders seen
in the ICU
• List some other selected clinical syndromes
4. HEMATOPOIESIS
• Hemat means blood & poiesis means to make/form
(formation of blood)
• Occurs during embryonic development & throughout
adulthood to produce & replenish the blood system.
6. Hematopoiesis process
• Two waves of hematopoiesis:-
• The primitive wave
• The definitive wave
• During the primitive wave of hematopoiesis, the
hemangioblast gives rise to primitive HSC-like
erythrocytes & angioblasts.
• During definitive hematopoiesis, the hemogenic
endothelium gives rise to multipotent HSCs, which
can give rise to all lineages of blood.
7.
8. Sites of Hematopoiesis
• Blood cell formation occurs in red marrow
(myeloid tissue)
• Skull & pelvis
• Ribs
• Sternum
• Proximal epiphyses humerus & femur
10. RBC Formation
• Erythropoiesis is the process which produces red
blood cells (erythrocytes).
• Life span- 100-120 days
• RBC start as immature cells in the bone marrow
and after approximately seven days of maturation
are released into the bloodstream.
12. Formation of WBC’s & Platelets
• WBC (leukocytes) are the cells of the immune system that
are involved in protecting the body against both infectious
disease and foreign invaders.
• All white blood cells are produced and derived
from multipotent cells in the bone marrow known
as hematopoietic stem cells.
• Produced in the bone marrow, the soft fatty tissue inside
bone cavities.
• Two types i.e. B cells (lymphocytes), are also produced in
the lymph nodes and spleen, and T cells are produced and
mature in the thymus gland.
13. CONT….
• Leukopoiesis, the process of making leukocytes,
is stimulated by various CSFs, which are
hormones produced by mature WBC.
• Platelets are formed from the cytoplasm of megakaryocytes
, their precursor cells, which reside in the bone marrow
• Platelets are produced during hematopoiesis in a sub-
process called thromopoiesis.
• Stored in the spleen.
• Thrombopoietin is a glycoprotein hormone produced by the
liver and kidney which regulates the production of platelets.
It stimulates the production and differentiation of
megakaryocytes
14.
15. Anemia
• Anemia (Hb <12 g/dL) is present in 95% of patients
admitted to the ICU, with about 1/3rd of them having
Hb <10 g/dL upon admission.
• Assessment: Time of onset, patient's ethnic origin,
concurrent illness, procedures undergone, drugs
patient is receiving, & history of transfusions.
• One practical approach is to classify anemia into
two major categories:
Anemia resulting from underproduction versus
Anemia due to increased destruction of red blood cells
(RBC)
16. Anemias secondary to marrow
underproduction
Decreased erythropoietin
production
• Renal disease
• Endocrine deficiency
• Starvation
Marrow failure
• Congenital dyserythropoietic
anemia
• Aplastic anemia
• Pure red cell aplasia
• Toxic marrow damage
Inadequate response to
erythropoietin
• Iron deficiency
• B12 deficiency
• Folic acid deficiency
• Anemia of chronic disease
• Marrow infiltration
• Sideroblastic anemia
• Myelodysplastic syndrome
17. Anemias secondary to increased
destruction
Acquired
Immune-mediated hemolytic anemia
Paroxysmal nocturnal hemoglobinuria
Hemolytic anemia due to red cell fragmentation (TTP,
DIC)
Hemolytic anemia due to chemical or physical agents
Infections
Acquired hemoglobinopathies (methemoglobinemia)
Hereditary
Congenital hemoglobinopathies (sickle cell disease)
Enzyme deficiency (G6PD, pyruvate kinase)
Red cell membrane defects (spherocytosis,
18. Anemia
• Obtain diagnostic tests prior to any transfusions:
CBC, including hematocrit, hemoglobin, MCV,
MCHC, a reticulocyte count & a stained blood
smear.
• In addition, serum bilirubin & LDH are useful to
determine the presence of hemolysis.
• If immune hemolysis is suspected, direct Coombs
test should be ordered; or
• If hemoglobinopathy is suspected, hemoglobin
electrophoresis should be obtained before
19. Leukopenia
• The term, leukopenia, refers to a total WBC count
of less than 4,000 cells/μL, whereas
granulocytopenia or neutropenia refers to a
circulating granulocyte count below 1,500 cells/μL.
• WBC & granulocyte levels are lower in some ethnic
groups, e.g., Africans, African Americans, &
Yemenite Jews, without any clinical significance.
• The clinical importance of granulocytopenia relates
to the associated increased risk of bacterial
infection. If the absolute neutrophil count is less
than or equal to 500 cells/μL, bacterial infection
becomes the rule.
20. Leukopenia
• Agranulocytosis implies severe neutropenia or a
complete absence of granulocytes.
• Three patient groups are most pertinent to critical
care situations:
a)Patients with neutropenia from primary bone
marrow diseases or cytotoxic treatment;
b)Patients in whom neutropenia exists alone or in
combination with other cytopenias as an aplastic
process; &
c)Patients with neutropenia or agranulocytosis
caused by immunologic mechanisms.
21. Thrombocytopenia
• Thrombocytopenia is a common laboratory abnormality in
ICU patients that has been associated with adverse
outcomes.
• Defined as a platelet count of less than 150 × 103 cells/μL.
• Associated with greater mortality.
• Symptoms include:
Easy or excessive bruising (purpura)
Superficial bleeding into the skin that appears as a rash
of pinpoint-sized reddish-purple spots (petechiae),
usually on the lower legs.
Prolonged bleeding from cuts.
Bleeding from your gums or nose.
23. • Depends on its cause & severity (Mild- may not
need treatment)
• Main goal is to prevent death & disability caused by
bleeding.
• Severe thrombocytopenia –
Medicines (corticosteroids, immunoglobulins or
rituximab)—1st course of treatment
Blood or platelet transfusions( active bleeding or a high
risk of bleeding)
Splenectomy (Mostly in ITP)
Treatment:
Thrombocytopenia
24. Erythrocytosis
• An abnormally increased red cell mass
• May require critical care due to complications of blood
hyper-viscosity or because of hemorrhagic or
thromboembolic complications that threaten some of these
patients.
• Usually a high value for hematocrit or hemoglobin
concentration.
25. Erythrocytosis
• True erythrocytosis results from one of two general
mechanisms:
Polycythemia vera (PV) is a clonal abnormality of bone
marrow stem cells resulting in autonomous overproduction
of red cells & often of granulocytes & platelets.
Secondary erythrocytosis results from excess erythropoietin
production in response to hypoxemia, abnormalities of
oxygen release from hemoglobin, or autonomous hormone
production (e.g., by renal or other tumors).
• When the RCM is expanded & the hematocrit increased,
blood viscosity is increased, & diminished blood flow, stasis,
thrombosis, & tissue hypoxia may ensue. On the other hand,
hemorrhagic tendency is also increased, particularly in PV,
where elevated platelet counts & abnormalities of platelet
26. Thrombocytosis
• Thrombocytosis: an elevated platelet count
• Unlike thrombocytopenia, the presence of
thrombocytosis predicts a favorable outcome in
ICU patients, whereas a blunted rise in platelet
count may be associated with worse outcome.
• Thrombocytosis in hospitalized patients is
classified according to its origin into
primary (or clonal) &
secondary (or reactive) forms.
27. Thrombocytosis
• Primary thrombocytosis - persistent elevation of platelet
count due to clonal thrombopoiesis
• E.g. In myeloproliferative disorders including essential
thrombocythemia, PV, myelodysplastic syndrome,
chronic myelogenous leukemia, & myelofibrosis.
• Secondary thrombocytosis
• Some of them are short-lived, such as acute bleeding,
infection, trauma or other tissue injury, & surgery;
• Other causes, such as malignancy, post splenectomy,
chronic infection, iron deficiency, or chronic inflammatory
disease may persist for a longer time.
• Whereas most patients have secondary thrombocytosis, a
higher platelet count & increased thromboembolic
28. Treatment :Thrombocytosis
• Based on risks for thrombosis or bleeding in the
presence of vasomotor symptoms. Patients at
increased risk should receive platelet-lowering
agents (e.g. hydroxyurea, anagrelide, or interferon-β
(IFN-β).
• Low-dose aspirin can be used for the relief of
vasomotor symptoms.
• Hydroxyurea is the recommended drug in patients
60 years of age or older.
• IFN-β is the cytoreductive agent of choice for
29. Leukocytosis
• Due to primary bone marrow disorders or secondary
disorders in response to acute infection or
inflammation.
• Secondary leukocytosis is physiologic & transient,
resolving after treating the underlying cause.
• Leukemoid reaction: persistent leukocytosis of more
than 50,000 cells/μL.
• Major causes include severe infections, severe
hemorrhage, acute hemolysis, hypersensitivity, &
malignancies (paraneoplastic syndrome).
30. • Leukocytosis due to a primary bone marrow
disorder with uncontrolled clonal growth of
immature cells can result in an emergency
situation known as the hyperleukocytosis
syndrome.
• This occurs in leukemic states when the white
blood cell count is high.
• The syndrome occurs more commonly in AML &
CML than in ALL, & occurs rarely, if ever, in CLL.
31. Leukocytosis
• S/s:- stupor, altered mentation, dizziness, visual blurring,
retinal abnormalities, dyspnea, tachypnea, & hypoxia;
Intracranial & pulmonary infarction or hemorrhage & sudden
death may occur.
• The level of the WBC count at which the syndrome appears is
variable
• A WBC count exceeding 100,000 cells/μL in AML or the
accelerated phase of CML is usually an alarming sign & an
indication for prompt treatment.
• Leukopheresis- To rapidly & safely decrease the WBC count.
• Chemotherapy initiated, & treatment with allopurinol & IV
hydration & urine alkalinization (for hyperuricaemia).
• Hydroxyurea (6 g by mouth) is frequently used initially to
32. Plasma Cell Dyscrasias
• Also termed plasma cell disorders & plasma cell proliferative
diseases
• A spectrum of progressively more severe monoclonal
gammopathies in which a clone or multiple clones of pre-
malignant or malignant plasma cells over-produce
a myeloma protein (an abnormal monoclonal antibody) or
portion thereof.
• Detection of one of these myeloma proteins in an individual's
blood or urine may indicate the presence of:
• A common & clinically silent disorder termed MGUS; or
• A hematological malignancy (multiple myeloma, or other
B cell associated neoplasm), that derives stepwise from
its MGUS precursor.
33. • Clinical importance is that it can be used to:
• Advise individuals on the likelihood of their condition
progressing to a malignant phase;
• Monitor for complications that may occur at any stage of
the dyscrasias; &
• Monitor for transitions to malignancy
• The presenting symptoms may include severe infection,
spinal cord compression, or hyperviscosity syndrome that
can lead to admission to the ICU.
• Total serum protein will be abnormally high on routine
chemistry blood test.
• Subsequent evaluation will reveal monoclonal gammopathy
of IgM in Waldenstrom macroglobulinemia or IgG/IgA in
34. • Hyperviscosity syndrome is rare when IgG or less
frequent when IgA, is the abnormal protein.
• The most common manifestations of the hyperviscosity
syndrome are neurologic (headache, visual
disturbances, hearing loss, vertigo, altered
consciousness (ranging from stupor to coma), paresis,
seizures, & peripheral neuropathy).
• A bleeding tendency may exist.
• The most rapidly effective form of therapy for
hyperviscosity from serum protein abnormalities is
plasmapheresis.
• At the same time, hydration & specific therapy for the
underlying disease should be started.
35. Coagulation
• Coagulation (also known as clotting) is the
process by which blood changes from a liquid to a
gel, forming a blood clot.
• It potentially results in hemostasis, the cessation of
blood loss from a damaged vessel, followed by
repair.
• It begins almost instantly after an injury to the blood
vessel damages the endothelium lining the vessel.
• The mechanism of coagulation involves activation,
adhesion, & aggregation of platelets along with
deposition & maturation of fibrin.
• Coagulation involves both a cellular (platelet) & a
36. Hemostasis
• It is an intricate system maintaining blood in fluid state
Reacts to vascular injury to stop blood loss & seal vessel
wall
• Involves blood vessels, platelets, clotting factors,
endothelium, & inhibitory/control mechanisms
Highly developed system of checks & balances
Designed to turn on when needed & to stop processes
before they go too far
37. Hemostasis
• Hemostasis is the process that leads to the stopping of
bleeding
• Leaking of blood through the endothelium initiates 2
processes:
• Primary Hemostasis
• Secondary Hemostasis
40. Coagulation Physiology
• Platelet activation
• Coagulation
cascade
• Tissue factor
pathway (extrinsic)
• Contact activation
pathway (intrinsic)
• Final common
pathway
– Co-factors
– Calcium & Phospholipids
– Vitamin K
– Regulators
– Protein C
– Antithrombin
– Tissue factor pathway
inhibitor (TFPI)
– Plasmin
– Prostacyclin
Coagulation involves the following:
41. Coagulation factors & related substances
Coagulation factors & related substances
Number and/or name Function Associated genetic disorders
I (fibrinogen) Forms clot (fibrin)
Congenital afibrinogenemia,
Familial renal amyloidosis
II (prothrombin)
Its active form (IIa) activates I, V, X, VII,
VIII, XI, XIII, protein C, platelets
Prothrombin
G20210A, Thrombophilia
III (tissue factor or tissue
thromboplastin )
Co-factor of VIIa (formerly known as
factor III)
IV Calcium
Required for coagulation factors to bind to
phospholipid (formerly known as factor IV)
V (proaccelerin, labile factor)
Co-factor of X with which it forms
the prothrombinase complex
Activated protein C resistance
VI Unassigned – old name of Factor Va
VII (stable factor, proconvertin) Activates IX, X congenital factor VII deficiency
VIII (Antihemophilic factor A)
Co-factor of IX with which it forms
the tenase complex
Haemophilia A
IX (Antihemophilic factor B or
Christmas factor)
Activates X: forms tenase complex with
factor VIII
Haemophilia B
42. Coagulation factors & related substances
Coagulation factors & related substances
Number and/or name Function Associated genetic disorders
X (Stuart-Prower factor)
Activates II:
forms prothrombinase complex with
factor V
Congenital Factor X deficiency
XI (plasma thromboplastin
antecedent)
Activates IX Haemophilia C
XII (Hageman factor) Activates factor XI, VII & prekallikrein Hereditary angioedema type III
XIII (fibrin-stabilizing factor) Crosslinks fibrin Congenital Factor XIIIa/b deficiency
von Willebrand factor Binds to VIII, mediates platelet adhesion von Willebrand disease
prekallikrein (Fletcher factor)
Activates XII & prekallikrein; cleaves
HMWK
Prekallikrein/Fletcher Factor deficiency
high-molecular-weight
kininogen (HMWK)
(Fitzgerald factor)
Supports reciprocal activation of XII, XI,
& prekallikrein
Kininogen deficiency
fibronectin Mediates cell adhesion
Glomerulopathy with fibronectin
deposits
antithrombin III Inhibits IIa, Xa, & other proteases Antithrombin III deficiency
heparin cofactor II
Inhibits IIa, cofactor for heparin
& dermatan sulfate ("minor
antithrombin")
Heparin cofactor II deficiency
43. Coagulation factors & related substances
Coagulation factors & related substances
Number and/or name Function Associated genetic disorders
protein C Inactivates Va & VIIIa Protein C deficiency
protein S
Cofactor for activated protein C (APC, inactive
when bound to C4b-binding protein)
Protein S deficiency
protein Z
Mediates thrombin adhesion to phospholipids &
stimulates degradation of factor X by ZPI
Protein Z deficiency
Protein Z-related
protease inhibitor (ZPI)
Degrades factors X (in presence of protein Z) & XI
(independently)
plasminogen Converts to plasmin, lyses fibrin & other proteins
Plasminogen deficiency, type I
(ligneous conjunctivitis)
alpha 2-antiplasmin Inhibits plasmin Antiplasmin deficiency
tissue plasminogen
activator (tPA)
Activates plasminogen
Familial hyperfibrinolysis & thro
mbophilia
urokinase Activates plasminogen Quebec platelet disorder
plasminogen activator
inhibitor-1 (PAI1)
Inactivates tPA & urokinase (endothelial PAI)
Plasminogen activator inhibitor-1
deficiency
plasminogen activator
inhibitor-2 (PAI2)
Inactivates tPA & urokinase (placental PAI)
cancer procoagulant
Pathological factor X activator linked to thrombosis
in cancer
44. Coagulation profile
• A Coagulation profile is used to assess blood
clotting function in patients. It is a screening test for
abnormal blood clotting because it examines the
factors most often associated with a bleeding
problem.
• The Coagulation Panel includes: Activated Partial
Thromboplastin Time (APTT) Prothrombin
Time/International Normalized Ratio (PT/INR)
• A coagulation screen is a combination
of screening laboratory tests, designed to provide
rapid non-specific information, which allows an
initial broad categorization of haemostatic
45. Coagulation profile
• The basic screen consists of:
Platelet count
Bleeding time for platelet function
PT/INR (Prothrombin time/International
Normalized Ratio) for the extrinsic pathway
aPTT (Activated Partial Thromboplastin time) for
the intrinsic pathway
TCT or fibrinogen assay for final common
pathway
46. Coagulation profile
• Two other tests are regularly performed at the same time:
Blood count, to detect other hematological abnormalities
LFTs to exclude liver disease as a cause of coagulation
factor deficiency
• May miss mild abnormalities but they will detect major
disorders.
• The results of these screening tests, in conjunction with
the clinical history, will then direct the selection of further,
more detailed & specific coagulation tests, such as:
Specific factor assays, like fibrin degradation products, D-
dimer, thrombin time, platelet aggregation, or
Specific factor inhibitor assays, like Protein
C, TFPI, Antithrombin etc.
47. Bleeding Time
• Used to measure the primary phase of hemostasis,
which involves platelet adherence to injured capillaries
& then platelet activation & aggregation.
• The bleeding time can be abnormal when the platelet
count is low or the platelets are dysfunctional. Causes
of abnormal bleeding time can be hereditary or
acquired.
• General interpretations of bleeding time are as follows:
1-9 minutes: Normal
9-15 minutes: Platelet dysfunction
More than 15 minutes: Critical; test must be
discontinued & pressure should be applied
48. PT/INR
• The PT/INR measures the extrinsic pathway.
• The prothrombin test specifically evaluates the presence of
factors VII, V & X, prothrombin, & fibrinogen. Deficiency of
any of these factors can prolong the PT.
• Vitamin K is a co-factor in the synthesis of functional factors
II (prothrombin), VII, IX & X
• The oral anticoagulant warfarin inhibits these vitamin k
dependent coagulation Factors (II, VII, IX & X).
• So, PT/INR is used to measure the efficacy of Warfarin
therapy.
• Normal PT lies within 0.9-12s (depends on the source of
thromboplastin used)- For adult males, normal range is 9.6–
11.8s seconds, while adult females, it is 9.5–11.3 seconds
49. PT/INR
• The result for a prothrombin time performed on a normal
individual will vary according to the type of analytical system
employed.
• The concept of INR started since different laboratories within
& outside the country use different thromboplastin reagents &
the baseline values are different with each reagent.
• The INR is the ratio of a patient's prothrombin time to a
normal (control) sample, raised to the power of the ISI value
for the analytical system being used.
• The ISI is usually between 0.94 & 1.4 for more sensitive &
2.0-3.0 for less sensitive thromboplastins. Normal ranges of
INR are:
2–3 for standard warfarin; 3–4.5 for high-dose warfarin
50. PTT/aPTT
• Partial thromboplastin time (PTT) & activated partial
thromboplastin time (aPTT) measure the overall speed at
which blood clots.
• Both are used to test for the same functions (the intrinsic
pathway of the coagulation)
• But, in aPTT, an activator is added that speeds up the
clotting time & results in a narrower reference range.
• Normal PTT require the presence of the following
coagulation factors: I, II, V, VIII, IX, X, XI & XII.
• Notably, deficiencies in factors VII or XIII will not be detected
with the PTT/aPTT test.
• The aPTT is considered a more sensitive version of the PTT
& is used to monitor the patient’s response to heparin
51. PTT/aPTT
– Heparin inhibits factors X & thrombin, by activating anti-
thrombin III thereby influencing the intrinsic pathway.
– The aPTT reagent influences the contact factor FXII &
triggers the intrinsic pathway.
– The reference range of PTT is 60-70 seconds & aPTT is 25-
40 seconds
PTT: >100 seconds or aPTT: >70 seconds signifies
spontaneous bleeding
During heparin therapy PTT/aPTT result is about 1.5 to 2.5
times the normal value.
– A high aPTT in the absence of heparin treatment can be due
to Haemophilia, which may require further testing.
52. TCT
• Also known as the thrombin clotting time (TCT).
• Measures the time it takes for a clot to form in the plasma of
a blood sample containing anticoagulant, after an excess
of thrombin has been added.
• Used to diagnose blood coagulation disorders & to assess
the effectiveness of fibrinolytic therapy.
• Compares the rate of clot formation to that of a sample of
normal pooled plasma.
• Thrombin is added to the samples of plasma. In blood
samples containing heparin, batroxobin (formerly reptilase) is
used instead of thrombin.
53. • If the time it takes for the plasma to clot is prolonged, a
quantitative (fibrinogen deficiency) or qualitative
(dysfunctional fibrinogen) defect is present.
• Normal values for TT are 12 to 16 seconds (generally
<22 seconds).
• If batroxobin is used, the time should be between 15 &
20 seconds.
• TCT can be prolonged by heparin, fibrin degradation
products, & fibrinogen deficiency or abnormality
54. Fibrinogen assay
• Fibrinogen is a soluble protein in the plasma that is broken
down to fibrin by the enzyme thrombin to form clots.
• The reference range for the different fibrinogen tests are as
follows:
• Fibrinogen antigen: 149-353 mg/dL
• Fibrinogen: 150-400 mg/dL
• Fibrinogen antigen/functional ratio: 0.59-1.23
• D-dimer: <250 mcg/L or <1.37 nmol/L
• Fibrinogen may be elevated in ACS, trauma, stroke etc. &
dereased in DIC; D-dimer may be elevated in conditions of
increased clotting activity in the body.
55. D- Dimer test
• An important test performed in patients with
suspected thrombotic disorders. While a negative
result practically rules out thrombosis, a positive
result can indicate thrombosis but does not rule out
other potential causes.
• To exclude thromboembolic disease where the
probability is low. In addition, it is used in the
diagnosis of the blood disorder disseminated
intravascular coagulation.
• The reference concentration of D-dimer is less than
0.5 µg/mL fibrinogen-equivalent units (FEU)
56.
57. Disseminated intravascular coagulation
• A condition in which blood clots form throughout the
body's small blood vessels. These blood clots can
reduce or block blood flow through the blood vessels
• Other names: Consumption coagulopathy;
Defibrination syndrome
• The clinical syndrome itself results from the activation
of blood coagulation, which then leads to excessive
thrombin generation.
• The final result of this process is the widespread
formation of fibrin thrombi in the microcirculation, with
resultant consumption of certain clotting factors &
platelets.
58. • Ultimately, this consumption generally results in the
development of significant bleeding due to the rate of
consumption outpacing the rate at which the clotting factors &
platelets are produced.
• The mechanisms involved can generally be considered in two
categories:
Those intrinsic processes that enzymatically activate
procoagulant proteins, &
Those that cause the release of tissue factor, which then
triggers coagulation.
• These complex events can lead to significant bleeding &
often complicate the management of an already critically ill
patient.
• Outlook for DIC depends on its severity & underlying cause.
60. DIC: Types
Acute DIC develops quickly (over hours or days) &
must be treated right away. The condition begins
with excessive blood clotting in the small blood
vessels & quickly leads to serious bleeding & even
cause death if it's not treated right away.
Chronic DIC develops slowly (over weeks or
months). It lasts longer & usually isn't recognized
as quickly as acute DIC. Chronic DIC causes
excessive blood clotting, but it usually doesn't lead
to bleeding. Cancer is the most common cause of
chronic DIC. Sometimes chronic DIC has no signs
or symptoms
61. • The suspicion that DIC is present usually stems from
one of two situations:
Unexplained generalized oozing or bleeding, or
Unexplained abnormal laboratory parameters of hemostasis
Laboratory Tests for the Diagnosis of DIC
Test Discriminator Value
Platelet count <80–100,000 cells/μL or a decrease of >50% from baseline
Fibrinogen <100 mg/dL or a decrease of >50% from baseline
PT >3 sec prolongation above ULN
FDPs >80 mg/dL
d-Dimer Moderate increase
Other tests CBC & Blood Smear (To reveal damaged RBCs)
62. DIC: Treatment
• Depends on its severity & cause.
• Main goals of treating DIC are to control bleeding &
clotting problems & treat the underlying cause.
• People who have acute DIC may present with
severe bleeding that requires emergency treatment
in a hospital
• They may need blood transfusions, medicines,
oxygen therapy (through nasal prongs or a mask),
& other life-saving measures like mechanical
ventilation via ET tube.
• People who have chronic DIC may need
anticoagulants
63. DIC: Treatment
Includes the use of several component blood products.
PRBCs are given in the face of active bleeding.
Fresh whole blood—that is, less than 24-48 hrs old—may be
given to replete both volume & oxygen-carrying capacity, &
provide coagulation proteins, including fibrinogen, &
platelets.
Platelet transfusions to maintain counts up to 40,000 to
80,000 cells/μL
If the serum fibrinogen level is less than 75-50 mg/dL,
repletion with cryoprecipitate to raise plasma levels to 100
mg/dL or higher is the goal.
A reasonable starting dose is one bag of cryoprecipitate for
every 10 kg body weight every 8 to 12 hours
Goal of blood component therapy is to produce clinical
64. DIC: Treatment
• Pharmacologic therapy for DIC has two primary aims:
To “turn off” ongoing coagulation so that repletion of
coagulation factors may begin, &
To impede thrombus formation & ensuing ischemic injury.
• Two new recombinant blood products have been recently
developed that have some usefulness in the treatment of
DIC.
Recombinant-activated protein C
Recombinant-activated factor VII (rhfVIIa)
• Other anticoagulant molecules such as heparin &
antithrombin III & thrombolytic agents are also used.
65. Liver disease/hepatic insufficiency
• In liver disease, the synthesis of several plasma
coagulation proteins is impaired including factors II, V,
VII, IX, & X.
• Fibrinogen synthesis by the liver usually can be
maintained at levels that prevent bleeding until terminal
liver failure supervenes. However, the function of
fibrinogen synthesized by a diseased liver may not be
normal (i.e., a dysfibrinogen).
• Factor XIII activity also is often decreased in the setting
of hepatocellular disease.
• Also, many patients with liver disease, particularly
cirrhosis, have increased fibrinolytic activity &
increased risk for development of DIC.
66. Liver disease/hepatic insufficiency
No active bleeding: No specific therapy is required.
Prolonged PT (in a postoperative state or are scheduled for
an invasive procedure): FFP provides the most immediate
source of specific coagulation factors (i.e., factor VII), &
usually corrects an isolated mild PT prolongation.
Platelet transfusions also may be required if the platelet
count is <40,000 to 80,000 cells/μL
Cryoprecipitate is required only if fibrinogen levels are <50
to 100 mg/dL, or if there is documentation of a significant
dysfibrinogenemia.
Vitamin K deficiency also is common & replacement may be
needed.
Recombinant human-activated factor VII (rhfIIa) infusions
67. Vitamin K deficiency/depletion
Causes :
• Use of broad-spectrum antibiotics
• Poor nutrition preceding or subsequent to ICU admission
• Use of parenteral nutrition without vitamin K
supplementation.
• Although malnutrition also may contribute to the development
of vitamin K deficiency, this usually requires 1 to 2 weeks to
develop in the complete absence of vitamin K intake.
• Fat malabsorption states, (including cystic fibrosis, some
biliary tract & intrinsic small bowel disease )may be
associated with vitamin K deficiency.
The reference range of vitamin K is 0.2-3.2 ng/mL
68. Vitamin K deficiency/depletion
Management
Repletion, usually by IV or s/c routes in critically ill patients.
Started when the PT abnormality is detected & vitamin K
deficiency is thought to be responsible.
The risk of anaphylactoid reactions with IV use is markedly
reduced when the drug is given as a piggyback infusion over
30 to 45 minutes in a small volume of fluid.
Usual dose in adults is 10 to 15 mg IV or s/c; 1 to 5 mg in
young children, & up to 10 mg in older children.
In an otherwise healthy person, the PT should correct within
12 to 24 hours after this dose.
If the PT does not correct within 72 hours after three daily
doses of vitamin K, intrinsic liver disease should be
suspected. Further administration of vitamin K is of no
69. Massive transfusion syndrome
• Transfusion of large quantities of blood can result in a
multifactorial hemostatic defect.
• Washout of plasma coagulation proteins & platelets
(resulting from the transfusion of large amounts of stored
blood products devoid of clotting factors & platelets)
• It may be exacerbated by the development of DIC with
consequent factor consumption, hypothermia, acidosis, or
rarely, by citrate toxicity or hypocalcemia.
• These variables often act in combination to cause a
coagulopathic state.
• Factors V & VII have short shelf half-lives & are often
deficient in blood that has been banked longer than 48
hours.
70. Massive transfusion syndrome
• The development of a washout coagulopathy is directly
dependent on the volume of blood transfused relative to the
blood volume of the patient.
• The therapeutic approach to patients who develop a
coagulopathy from massive transfusion is supportive.
• Platelets & FFP are given to replete the components of
coagulation that are typically lacking.
• Cryoprecipitate may be given when fibrinogen depletion is
thought to be a major contributor to the observed bleeding.
71. Anticoagulant overdose
(heparin,warfarin)
• Heparin overdose- Protamine sulfate, 1 mg of protamine
neutralizes approximately 100 units of heparin.
• Given by slow IV push over 8 to 10 minutes. A single dose
should not exceed 1mg/kg, with a 50mg maximum dose.
• This dose may be repeated, but no more than 2 mg/kg, to a
100mg maximum dose, should be given as a cumulative dose
without rechecking coagulation parameters.
• LMWH is not consistently neutralized by protamine, so
invasive procedures should not be performed within 24 hours
of administration.
• Bleeding following LMWH therapy has been treated effectively
with rhfVIIa (recombinant human activated factor VIIa)
72. Anticoagulant overdose
(heparin,warfarin)
• Warfarin overdose- Vitamin K
• When over-anticoagulation with warfarin presents with
bleeding, immediate reversal is usually mandated.
• The treatment of choice is FFP, which provides prompt
restoration of the deficient vitamin K–dependent coagulation
proteins, along with restoration of hemostatic function.
• 10 -15 mL/kg of FFP are usually sufficient to produce
significant correction of the PT.
• Vitamin K also may be administered in less acute situations
• For severe bleeding or bleeding not controlled by FFP
infusions, rhfVIIa has been used successfully.
73. Thrombocytopenia (drug-induced,
immunologic) & Acquired platelet defects
(drug-induced)
• Because many of the adverse drug-related platelet effects
are reversible, unnecessary medications should always be
discontinued promptly when platelet function seems
impaired.
• In fact, as a general rule, it is never acceptable to leave a
nonessential agent on the patient's medication list simply
because it is benign; any drug in this category must be
discontinued.
• Uremia can also cause a reversible impairment of platelet
function, although the “toxin” responsible for this defect is
not well defined (possibly due to defects in von Willebrand
factor).
74. • Also, thrombotic events are also increased in patients with
uremia.
• The primary therapy is dialysis.
• Cryoprecipitate
• Cryoprecipitate or DDAVP increase the plasma concentration
of the large multimeric forms of von Willebrand factor, thus
improving platelet adhesion.
75.
76. TTP/HUS
• HUS is more commonly seen in children, & is characterized
by a prodrome of fever & diffuse, often bloody, diarrhea.
• TTP is characterized by the pentad of microangiopathic
hemolytic anemia (MAHA), thrombocytopenia, neurologic
symptoms, fever, & renal dysfunction.
• Whereas only 40% of patients will display the full pentad, up
to 75% will manifest a triad of MAHA, neurologic symptoms,
& thrombocytopenia.
• This disorder is felt to be due to the absence or inhibition of
a vWf cleaving protease (ADAMTS13), resulting in the
circulation of unusually large vWf multimers, which can
induce or enhance the pathologic adhesion of platelets to
the endothelium.
77. • Although neither generally produces a coagulopathic state,
both are characterized by marked microangiopathy &
microvascular thrombosis.
• Therapy for HUS, including renal replacement measures, is
supportive.
• Neither plasma infusion nor plasma exchange appears to
be beneficial in the treatment of HUS.
• The therapy of choice for TTP is plasma exchange by
apheresis.
• Platelet transfusions are generally not recommended
except in the case of major bleeding.
78. Deep venous thrombosis
• A condition in which thrombus forms in the deep veins
of the legs, arms & pelvis (usually in the leg), which in
some cases then breaks free & enters the circulation as
an embolus, finally, lodging in & completely obstructing
a blood vessel.
ETIOLOGY
• DVT usually originates in the lower extremity venous
level, starting at the calf vein level & progressing
proximally to involve popliteal, femoral or iliac system.
• 80-90% of pulmonary emboli originates here
79. DVT Presentation
• In majority of cases, only one leg
affected.
• Calf pain or tenderness or both
• The skin of the affected leg may feel
warm
• Swelling below knee in distal DVT & upto
groin in proximal DVT
• Superficial venous dilation: Skin may go
red especially below the knee behind the
leg
• Skin may be discolored
• Cyanosis in c/o severe obstruction
• Leg fatigue
80. Deep venous thrombosis
• Palpate distal pulses & evaluate
CRT to assess limb perfusion.
• Move & palpate all joints to detect
acute arthritis or other joint
pathology
• Homan’s sign: Pain in the posterior
calf or knee with forced dorsiflexion
of the foot while the knee is fully
extended.
• Examine for signs suggestive of
underlying predisposing factors.
81. Signs of Pulmonary embolism
• Breathlessness- This may develop slowly or come on
suddenly
• Chest pain- Usually more severe during inhalation, eating,
coughing, stooping or bending over. During exertion, the
pain will get worse, & won’t go away when the patient rests
• Coughing may produce bloody or blood stained sputum
• Wheezing
• Light headedness, & sometimes even fainting
• Unexplained anxiety
• Accelerated heartbeat
82. Diagnostic studies
• Blood tests
D-dimer assays:- Have predictive value for DVT
INR:- Useful for guiding Mx of pts with known DVT who
are on Warfarin
• Imaging studies
Invasive
• Venography- Gold standard for DVT diagnosis
• Radio-labeled fibrinogen- To distinguish a new clot
from an old one
Non-invasive
• Ultrasound- Duplex USG used; distinguishes other
causes of leg swelling
• MRI- Distinguishes a mature from an immature clot
83. DVT Prophylaxis
• Identify at risk patients & specific
risk factors (e.g. Drugs)
• Prevent dehydration
• Passive leg exercises
• Encourage early mobilization
• Elevation of foot end to increase
venous return
• Use of anti-thromboembolism
stockings & sequential
compression devices in at-risk pts
• UFH 5000 units s/c Q8-12h
• LMWH 0.4-0.6 mg s/c OD
84. Treatment
• Primary objectives of treatment of DVT are:
Prevent pulmonary embolism
Reduce morbidity
Prevent/minimize the risk of developing post-phlebitic
syndrome
• Treatment options
Anticoagulation:- Heparin, Warfarin
Compression devices
Thrombolytic therapy for DVT
Surgery for DVT
85. Duration of anticoagulation in DVT
• Transient cause & no other risk factors: 3 months
• Idiopathic: 3-6 months
• Ongoing risk (e.g. malignancy): 6-12 months
• Recurrent PE or DVT: 6-12 months
• Patients with high risk of recurrent thrombosis
exceeding risk of anticoagulation: indefinite duration
(subject to review)
86. Surgery for DVT
• Open surgical thrombectomy- Reserved as last resort in pts
with threatened limb loss secondary to extensive DVT when
anticoagulant therapy is ineffective, unsafe or
contraindicated.
• Filters can be inserted in vena cava to stop blood clots from
reaching lungs
These pulmonary emboli removed at autopsy
look like casts of the deep veins of the leg
where they originated
Vena cava filter
87. HIT- Heparin induced
thrombocytopenia
• Heparin occurs naturally in the human body. But, development
of HIT antibodies suggests that heparin sulfate acts as a
hapten, & thus targeted by the immune system.
• Development usually takes about 5 days. These antibodies
form a complex with heparin in the bloodstream. The tail of the
antibody then binds to a protein on the surface of platelets.
• This leads to platelet activation, which initiate clot formation &
platelet consumption leading to fall in platelet counts
• In strongly suspected or proven HIT, anticoagulation is
provided with:
LMW heparin (Enoxaparin, Dalteparin, Ardeparin)
Lepirudin (Recombinant Hirudin:- Direct thrombin inhibitor)
Argatroban (Direct thrombin inhibitor)
88. Coronary thrombosis/acute
myocardial infarction
• Coronary thrombosis is the formation of a blood clot inside a
blood vessel of the heart. This blood clot restricts blood flow
within the heart. It is associated with narrowing of blood vessels
subsequent to clotting.
• Thrombosis in the heart can lead to an acute MI. Symptoms,
especially when the artery is blocked by ≥ 70%, include:
Chest pain, Heart palpitations
Shortness of breath, Sweating
Weakness or dizziness
Nausea
• Treatment- MONA, Thrombolytic therapy, Antiplatelet
medications
90. Lupus anticoagulant
• The lupus anticoagulant is an antiphospholipid antibody
directed against phospholipids or lipoproteins, & produces
prolongation of the PT, aPTT, or the measured recalcification
time of platelet-rich plasma.
• The presence of an antiphospholipid antibody such as
the lupus anticoagulant & anticardiolipin antibody in an
individual is associated with a predisposition for blood
clots/thrombosis.
• Lupus anticoagulant testing may be used to help determine
the cause of: An unexplained thrombosis in a vein or artery,
recurrent miscarriages or unexplained prolonged PTT.
91. Lupus anticoagulant
• Lupus anticoagulant was originally described in patients
with SLE.
• But now, lupus anticoagulants or anticardiolipin antibodies,
or both, have been demonstrated in large percentages of
patients with HIV infection, hemophilia A, disorders
accompanied by chronic & acute inflammation etc.
• Thrombosis, when it occurs, is equally likely to be venous
or arterial. Venous thrombosis is more common in the
extremities whereas arterial thrombosis is more common in
the central nervous system.
• Stroke, myocardial infarction, & pulmonary embolization are
also seen in patients with the lupus anticoagulant.
92. Reactive hyper-fibrinogenemia &
dysfibrinogenemia
• Hyper-fibrinogenemia - A plasma fibrinogen concentration
greater than 800 mg/dL.
• In the clinical laboratory, fibrinogen is measured using a
functional assay. The time to clotting in this setting is
proportional to the amount of fibrinogen present in the
sample.
• Other parameters, like aPTT, PT, & the TT, are consequently
prolonged, suggesting a risk for bleeding despite a high
fibrinogen level.
93. • This can be evaluated by diluting the plasma to a normal
fibrinogen concentration using saline or defibrinated
plasma. These same clotting studies will now be normal.
• In patients with dysfibrinogenemia, clotting studies fail to
correct when either saline or defibrinated plasma dilutions
are undertaken, thus distinguishing them from patients with
reactive hyper-fibrinogenemia
94. OTHER SELECTED CLINICAL
SYNDROMES
• Hemophilia (A & B)
• Specific factor deficiencies associated with
specific diseases
• Amyloidosis, factor X; Gaucher, factor IX;
nephrotic syndrome, factor IX, antithrombin III
• Cyanotic congenital heart disease (polycythemia,
qualitative platelet defect)
• Depressed clotting factor levels (newborns)
95. Summary
• Hematopoiesis- Definition, sites, process (primary & definitive
wave)
• Various hematologic conditions seen in the ICU
Decreased blood counts- Anemia; Leukopenia;
Thrombocytopenia
Increased blood counts- Erythrocytosis; Thrombocytosis;
Leukocytosis
Other hematologic disorders- Plasma cell dyscrasias
• Coagulation & hemostasis- Definition, Types of hemostasis
• Coagulation physiology
• Various coagulation factors & related substances
• Monitoring of blood coagulation- coagulation profile (Bleeding
time, PT/INR, PTT/aPTT, TCT & Fibrinogen assay
96. Summary
• Various coagulation disorders seen in the ICU
Conditions a/w serious bleeding or a high probability of
bleeding- DIC; Liver disease/hepatic insufficiency; Vitamin K
deficiency/depletion; Massive transfusion syndrome;
Anticoagulant overdose (heparin, warfarin); Thrombocytopenia;
Acquired platelet defects
Thrombotic clinical syndromes- TTP/HUS; Deep venous
thrombosis; Pulmonary embolism; Coronary thrombosis/acute
MI
Laboratory abnormalities not a/w clinical bleeding- Lupus
anticoagulant; Reactive hyper-fibrinogenemia &
dysfibrinogenemia
• List of other selected clinical syndromes
97. REFERENCES
• Gabrielli, A. Layon, AJ. Mihae, Yu. (2009) Civetta, Taylor & Kirby's Critical
Crae (4th ed.). Wolters Kluwer; Lippincott williams & Wilkins; retrieved
from Ovid
• Marini, JJ. Wheeler, AP. (2006). Critical Care Medicine: The essentials
(3rd ed). Lippincott williams & Wilkins; retrieved from Ovid
• Tortora, GJ. Derrickson, BH. (2010). Principles of anatomy & physiology
(13th ed). Wiley; ISBN:- 1118050223, 9781118050224
• Jagannathan-Bogdan, M., & Zon, L. I. (2013).
Hematopoiesis. Development (Cambridge, England), 140(12), 2463–
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10.4103/lungindia.lungindia_54_16
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