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MEDICINE
1.4D BLEEDING DISORDERS & DISSEMINATED INTRAVASCULAR COAGULATION

STEPS OF NORMAL HEMOSTASIS

Platelet plug formation

Fibrin Clot formation - The immediate trigger for coagulation is

vascular damage that exposes blood to TF that is consitutively
expressed on the surfaces of subendothelial cellular
components of the vessel wall

Fibrinolytic system

THROMBOCYTOPENIA
Results from:

Decreased bone marrow production aplastic

anemia, leukemia

Hereditary or acquired

Sequestration hypersplenism

Increased platelet destruction ITP

Antithrombotic mechanism

Prevent clotting under normal circumstances

These mechanisms operate to preserve blood fluidity

and to limit blood clotting specific focal sites of
vascular injury

Antithrombotic effects of endothelium

Prostacyclin

Nitric oxide

EctoADPase/CD39
Antithrombotic Mechanisms

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APPROACH TO PATIENT
Do complete history and physical examination

Family history of thrombocytopenia

History of bleeding

Consider age

Drugs being taken

Enlarged spleen
INFECTION INDUCED THROMBOCYTOPENIA
Most common non-iatrogenic cause of thrombocytopenia
Infection can both affect both platelet production and survival
May or may not be associated with laboratory evidence of
intravascular coagulation
Platelets can contribute to both innate and adaptive immunity.

Enhancement of platelet-neutrophil interactions with

promotion of bacterial trapping by stimulating
Neutrophil Extracellular Traps (NETs)

Confers resistance to Gram positive and

gram negative bacteria

Platelet factor V contributes to resistance of Group A

strep

Enhance cytolytic T-cell proliferation and antibody

production by Bells

Bind to malarial-infected RBCs and suppress growth

and destroy the parasite.

DRUG INDUCED THROMBOCYTOPENIA

Genetic or environmental factors both influence susceptibility to
drugs
Discontinuation of causative drug(s) is the main treatment
strategy
Glucocorticoids may be used in some patients
Heparin-induced thrombocytopenia (HIT)

May be severe and life-threatening

Immune-mediated

HEPARIN INDUCED THROMBOCYTOPENIA

Results from antibody formation to a complex of platelet factor
4 and heparin
There is markedly increased risk of thrombosis

Arterial and venous system may be affected

Ten times more common with unfractionated heparin as
compared to LMWH
Most patients develop HIT after exposure to heparin for 5-14
days, but may occur before 5 days if with prior exposure
Laboratory testing: ELISA
Management/Treatment

Early recognition and prompt discontinuation of

heparin
Imaging studies to evaluate thrombosis
Shift anticoagulant

Direct thrombin inhibitors (bivalirudin,

lepirudin, argatroban)

Fondparinux effective but not yet

approved for this indication
Overlap with warfarin

IMMUNE THROMBOCYTOPENIC PURPURA

Also known as Immune-mediated thrombocytopenia
Acquired disorder in which there is immune-mediated
destruction of platelets and possibly inhibition of platelet
release from the megakaryocyte.
In children- acute disease, most commonly following an
infection, and with a self-limited course.
In adults - more chronic course (>6 months)
ITP is termed secondary if it is associated with an underlying
disorder

Autoimmune disorders, particularly systemic lupus

erythematosus (SLE), and infections, such as HIV
and hepatitis C, are common causes.
The association of ITP with Helicobacter pylori infection is
unclear.
Clinical Presentation

Mucocutaneous bleeding - oral mucosa,

gastrointestinal bleeding

low, often very low, platelet count,

Patients usually present either with ecchymoses and

petechiae, or with thrombocytopenia incidentally
found on a routine CBC.

Heavy menstrual bleeding, may be present.

Rarely, life-threatening, including central nervous

system, bleeding can occur.
Laboratory Evaluation

Laboratory testing for antibodies (serologic testing) is

usually not helpful.

Bone marrow examination

older adults (usually >60 years) or

those who have other signs or laboratory

abnormalities not explained by ITP, or in

no response to initial therapy.

Laboratory testing is performed to evaluate for secondary
causes of ITP

Testing for HIV infection and hepatitis C (and other

infections if indicated)

SLE

serum protein electrophoresis, and immunoglobulin

levels

IgA deficiency or monoclonal gammopathies

direct antiglobulin testing (Coombs test) to rule out

combined autoimmune hemolytic anemia with ITP
(Evans syndrome).
Treatment

Not all patients diagnosed with ITP require treatment

For those that need intervention

IVIg

Glucocorticoids

Anti-RhD

Rituximab

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1.4D BLEEDING DISORDERS & DISSEMINATED INTRAVASCULAR COAGULATION

TPO Mimetic Drugs Romiplostim,

Eltrombopag
Splenectomy
Azathioprine
Danazol
Vinca alkaloids
Cyclophosphamide

THROMBOTIC THROMBOCYTOPENIC PURPURA

Form of thrombotic microangiopathy in which tissue injury can
affect any organ but often results in neurologic damage and
fever
Renal involvement is common but oliguric renal failure is not.
Usually associated with acquired antibodies that inhibit
ADAMTS13
Inherited TTP Upshaw-Schulman syndrome

Peak incidence between 30 and 50 years

Female preponderance (F:M = 2:1) below age 50 years, but
ratio apporoaches equality after 60 years
No geographic or racial distribution has been defined.
TTP is more common in patients with HIV and in pregnant
women.
Medication-related microangiopathic hemolytic anemia

Secondary to antibody formation ticlopidine,

clopidogrel)

Direct endothelial toxicity - cyclosporine, mitomycin

C, tacrolimus, quinine
Clinical Features

Acute or insidious onset

Systemic microvasular thrombosis can affect any

organ

Thrombocytopenia without hemolytic anemia may

herald onset of disease

Anemia in almost all patients

Thrombocytopenia is typically severe

Treatment

Plasma Exchange

Glucocorticoids

Antiplatelet agents

Immunosuppresive therapy Rituximab, Vincristine,

Cyclosporine

Splenectomy
HEMOLYTIC UREMIC SYNDROME
Characterized by

acute renal failure

Microangiopathic hemolytic anemia

Thrombocytopenia
Seen predominantly in children <10 years old
In most cases is preceded by an episode of diarrhea, often
hemorrhagic in nature.
Escherichia coli O157:H7 is the most frequent etiologic
serotype.
HUS not associated with diarrhea (termed DHUS) is more
heterogeneous in presentation and course.
BLEEDING DISORDERS
HEMOPHILIA
X linked recessive disorder
Males are affected, Females are carriers
F8 gene Hemophilia A
F9 gene Hemophilia B
Clinically, hemophilia A and hemophilia B are indistinguishable
Classification of Severity

severe (<1%),

moderate (15%)

mild (630%

Most carriers have approximately 50 percent factor VIII activity

and experience no bleeding symptoms, even with surgical
procedures.
Clinical Features

Characterized by excessive bleeding into various

tissues of the body, including soft-tissue hematoma
and hemarthrosis

Recurrent hemarthroses are characteristic of the

disease

Severely affected patients frequently experience

spontaneous bleeding without known trauma other
than usual activities
Hemarthroses

Bleeding into joints accounts for approximately 75%

of bleeding episodes in severely affected patients
with hemophilia.

Joint affectation: knees>elbows>ankles>

shoulders>wrists>hips.

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1.4D BLEEDING DISORDERS & DISSEMINATED INTRAVASCULAR COAGULATION

Hinge joints are much more likely to be involved than

are ball-and-socket joints.
Hemarthroses usually occur when an affected child
begins to walk.
Target Joint
Iron deposition from residual blood is a major factor
in the pathogenesis of hemophilic arthropathy

Soft tissue hematomas

Pseudotumor (Blood cysts)
Hematuria
Neurologic complications
Mucous membrane hemorrhage
Dental and Surgical Bleeding
Laboratory features

prolonged activated partial thromboplastin time

(aPTT)

The prothrombin time (PT), thrombin clotting time

(TCT), and bleeding time (BT) are normal

some investigators have reported minor increases in

the BT.
Treatment

Factor replacement

Prophylactic to prevent bleeding, esp

hemarothrosis

In response to bleeding

Dose computed depending on

site of bleeding

Cryoprecipitate for Hemophilia A; Cyrosupernate for

Hemophila B

FFP

DDAVP

Antifibrinolytic drugs EACA, Tranexamic acid

Complications

Inhibitor formation

Infectious disease Hepa B, Hepa C, HIV

VON WILLEBRAND DISEASE
Most common inherited bleeding disorder
Role of VWF:

major adhesion molecule that tethers the platelet to

the exposed subendothelium;

binding protein for FVIII, resulting in significant

prolongation of the FVIII half-life in circulation

Clinical Features

Mucocutaneous bleeding is the most common

symptom

Epistaxis

Easy bruising

Menorrhagia

Gastrointestinal bleeding

Thrombocytopenia for VWD type 2B

Not all patients with low VWF levels have bleeding symptoms.
Whether patients bleed or not will depend on the overall
hemostatic balance they have inherited, environmental
influences and the type of hemostatic challenges.
Many factors modulate both VWF levels and bleeding
symptoms.

Blood type, thyroid hormone status, race, stress,

exercise, and hormonal influences.

Patients with type O blood have VWF protein levels

of approximately one-half that of patients with AB
blood type;
Laboratory Testing

Factor VIII levels generally decreased

VWF Antigen

Ristocetin Cofactor Activity

Ristocetin induced platelet aggregation

Multimer Analysis

Bleeding time
Treatment

DDAVP releases VWF and Factor VIII from

endothelium

VWF replacement therapy

Antifibrinolytic therapy EACA, Tranexamic Acid

DISSEMINATED INTRAVASCULAR COAGULATION
Clinicopathologic syndrome in which widespread intravascular
coagulation occurs as a result of exposure or production of
procoagulants insufficiently balanced by natural anticoagulant
mechanisms and endogenous fibrinolysis.
Perturbation of the endothelium in the microcirculation along
with stimulated inflammatory cells and release of inflammatory
mediators play a key role
May cause tissue ischemia from occlusive microthrombi, and
bleeding from the consumption of platelets and coagulation
factors and, in some cases, an excessive fibrinolytic response.

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1.4D BLEEDING DISORDERS & DISSEMINATED INTRAVASCULAR COAGULATION

Pathology

Diffuse multiorgan bleeding

Hemorrhagic necrosis

Microthrombi in small blood vessels,

Thrombi in medium and large blood vessels

Organs most frequently involved by diffuse

microthrombi are the lungs and kidneys, followed by
the brain, heart, liver, spleen, adrenal glands,
pancreas, and gut
Causes are

Bacterial sepsis

Malignant disorders such as solid tumors or acute

promyelocytic leukemia

Obstetric causes - abruptio placentae, amniotic fluid

embolism.

Trauma- brain

The exposure of blood to phospholipids

from damaged tissue, hemolysis, and
endothelial damage are all contributing
factors to the development of DIC in this
setting.
Central mechanism - uncontrolled generation of thrombin by
exposure of the blood to pathologic levels of tissue factor
Simultaneous suppression of physiologic anticoagulant
mechanisms and abnormal fibrinolysis further accelerate the
process
Clinical Manifestation

Most common findings - bleeding ranging from

oozing from venipuncture sites, petechiae, and
ecchymoses to severe hemorrhage from the
gastrointestinal tract, lung, CNS.

In chronic DIC, the bleeding symptoms are discrete

and restricted to skin or mucosal surfaces.

Hypercoagulability - occlusion of vessels in the

microcirculation and resulting organ failure.

Thrombosis of large vessels and cerebral embolism

can also occur.

Hemodynamic complications and shock

are common in acute DIC.

The mortality ranges from 30 to >80%

depending on the underlying disease, the
severity of the DIC, and the age of the
patient

Increased D-dimer test is more specific for detection

of fibrinbut not fibrinogendegradation products
and indicates that the cross-linked fibrin has been
digested by plasmin.

High-grade DIC is also associated with levels of

antithrombin III or plasminogen activity <60% of
normal.

Chronic DIC

Low-grade, compensated DIC in clinical situations

including giant hemangioma, metastatic carcinoma,
or the dead fetus syndrome.

Elevated plasma levels of FDP or D-dimer

Normal or deranged aPTT, PT, and fibrinogen

values.

Mild thrombocytopenia or normal platelet counts

Red cell fragmentation is often detected but at a

lower degree than in acute DIC.

Treatment

Treat underlying condition

Blood component therapy to manage bleeding

FFP for prolonged PT/PTT

Cyroprecitpitate for low levels of fibrinogen

Platelet concentrate for those with very low

platelet counts (usually <50,000)

Low dose continuous infusion Heparin for patients

with recognized thrombosis

Controversial and no proven survival

benefit

Antifibrinolytic drugs
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Laboratory Findings

Prolongation of PT and/or aPTT;

Platelet counts 100,000/L3, or a rapid decline in

platelet numbers; the presence of

Schistocytes in the blood smear;

Elevated levels of FDP - sensitive test for DIC is the

FDP level.

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