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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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Medicine

1.4D BLEEDING DISORDERS & DISSEMINATED INTRAVASCULAR COAGULATION

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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Medicine

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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Medicine

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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Medicine

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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