Bleeding disorders

Outlines:
● Overview of Hemostasis.
● Congenital Bleeding Disorders.
● Acquired Bleeding Disorders.
● Platelet Disorders (Number & Function).
● Approach to the bleeding Pt.
● Management of Bleeding Pt.

Done by :
Team leader: Salem Al-Ammari

Team members: - Abdulrahman alaujan. -Khalid Almutairi

-Mohammed Alasqah

Revised by :
Aseel Badukhon

Resources :
● 437 slides | Not Same 436’s slides
● Teamwork 436
● Doctor notes | Prof.Ghada ElGohary
● QWord bank
● Amboss

Important Notes Golden Notes Extra Book

What is a Bleeding Disorder?
Bleeding disorders are a group of disorders that share the inability to form a
proper blood clot. They are characterized by extended bleeding after injury,
surgery, trauma or menstruation.

This video would be helpful:

https://youtu.be/GAcAPDVD3C0

Hemostasis
The process through which bleeding is controlled at a site of damaged or disrupted
endothelium.

A dynamic interplay between

● Cellular Components: ( PLTs & Endothelium )
● Plasma Proteins Components: 3 protein systems
○ Blood Coagulation ( Clot Formation )
○ Fibrinolysis ( Clot Lysing )
○ Anticoagulant ( Regulating )

Lab Tests
BV Injury
•CBC-Plt
•BT,(CT)
•PT
•PTT
Ti cto
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Blood Vessel Platelet Coagulation

Constriction Aggregation Cascade
Primary hemostatic plug
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Platelet activation
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Plt Study
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Fi Morphology
Stable Hemostatic Function
Plug Antibody
PLATELETS
● Produced in the Bone Marrow by fragmentation of the cytoplasm of megakaryocytes.
● Each megakaryocytes rise Plt from 1000 to 5000.
● Time interval from differentiation of the human stem cell to the production of Plts ( ~ 10 days )
● Thrombopoietin is the major regulator of Plt production via c-MPL receptor (produced by Liver &
Kidney)
● Normal PLT counts ( 150 – 400 x 10⁹ ) (Important)
● PLT Life Span ( 7 – 10 days )

PLTs Ultrastructure
Extremely small & discoid (3 x 0.5 µm in diameter)
3 types of storage granules
α Granules
● Clotting Factors
● VWF
● PDGF
● ILGF1
Dense Granules ( δ Granules )
● ADP & ATP
● Serotonin
● Histamine
● Ionized Ca
Lysosomes
● Hydrolytic enzymes
PLTs Functions
I.Adhesion ( PLT – Vessel Wall ) <- VWF through GP Ib/IX/V (synthesized in endothelial cells &
megakaryocytes / stored in storage granules of endothelial cells & α granules of Plt /
Rise with stress, exercise, adrenaline, infusion of DDAVP)

II.Aggregation ( cross linking of PLT – PLT ) <- VWF & Fibrinogen through GP IIb/IIIa receptors

III.Release Reaction & Amplification ( aggregation formation & stabilization )

● release of α granules contents, & ADP from dense granules
● formation of Thromboxane A2 by various agonists induces intracellular signaling.

PLTs Inhibitors
PLT Function Inhibitors
Prostacyclin (PGI₂);
● synthesized by vascular endothelial cells
● potent inhibitor of PLT aggregation & causes vasodilation by rising cAMP
● prevents Plt deposition on normal vascular endothelium
Nitric Oxide (NO);
● released from endothelial cells, macrophages, & Plt
● inhibit Plt activation & promotes vasodilation

Clotting Factors
 Fibrinolysis

Great video explaining coagulation cascade:

https://youtu.be/JoPQEDt1b0w

HEMOSTASIS
DEPENDENT UPON:
Vessel Wall Integrity (because we need vascularity. Vasculitis and CT disorders will affect that causing
bleeding tendency)
Adequate Numbers of Platelets
Proper Functioning Platelets
Adequate Levels of Clotting Factors (Any defect of any of the factors will cause massive bleeding)
Proper Function of Fibrinolytic Pathway

Hemostatic Phases
I. Vascular Phase:
release of locally active vasoactive agents (Endothelin, Thromboxane A2, Fibrinopeptides) 🖝
Vasoconstriction at the site of injury 🖝 reduced blood flow

II. Platelet Phase: Plt Adhesion & Aggregation (via VWF, ADP, TXA2) 🖝 formation
of PLT Plug

III. Plasma Coagulation Phase: Propagation of the clotting process by the coagulation
cascade 🖝 formation of Fibrin Clot

IV. Fibrinolysis Phase: Termination of clotting by antithrombotic control mechanisms

& removal of the clot
 Responsible for initial formation of
Primary Hemostasis: platelet plug it’s affected in case of:
1. Endothelium Injury Thrombocytopenia, von willebrand
2. Platelet disease and also in platelet function
3. Von Willebrand Factor disorder

Secondary Hemostasis:
1. Clotting Factors
2. Soluble Protein Fibrinogen
converted to insoluble Fibrin

Primary Hemos.

Secondary Hemos.
 BLEEDING DISORDERS
LABORATORY EVALUATION
(to know the source of bleeding)
Taking Hx
Congenital:
● PLATELET COUNT - Family Hx
● BLEEDING TIME (BT) - Since Childhood (hemophilia &
● PROTHROMBIN TIME (PT) clotting factors)
Acquired:
● PARTIAL THROMBOPLASTIN TIME (PTT)
- Middle age onset
● THROMBIN TIME (TT) - Cause leading to DIC

BLEEDING TIME:
PROVIDES ASSESSMENT OF PLATELET COUNT AND FUNCTION

NORMAL VALUE 2-8 MINUTES

PROTHROMBIN TIME (PT):

Measures Effectiveness of the Extrinsic Pathway

NORMAL VALUE 10-15 SECS

Prothrombin time tests the extrinsic and final common pathways

Prolongation in:
● Liver disease
● vitamin K antagonism (i.e. warfarin) and deficiency (In Bariatric surgery or removal of stomach)
● Disseminated intravascular coagulation (In severe infection or malignancy)
● Factor VII, X, V, II and fibrinogen defect

PARTIAL THROMBOPLASTIN TIME

Measures Effectiveness of the Intrinsic Pathway

NORMAL VALUE 25-40 SECS

Activated partial thromboplastin time

Tests the intrinsic and common pathways

Prolongation in:
● Liver disease
● Disseminated intravascular coagulation Q) Pt on Heparin, what is followed is
● Heparin therapy prolongation of PTT
● Vitamin K antagonism or deficiency
● Factor XII, XI, IX, VIII, X, V, II, and fibrinogen defect
 THROMBIN TIME Not always available, and need accuracy

● Time for Thrombin To Convert Fibrinogen to Fibrin

● A Measure of Fibrinolytic Pathway

NORMAL VALUE 9-13 SECS

Thrombin time evaluate fibrinogen and for inhibition of thrombin action

Prolongation in:
● Hypofibrinogenaemia Hypofibrinogenaemia :
● Dysfibrinogenaemia (http://www.fmshk.com.hk/hkabth) Congenital deficiency which has
● Heparin therapy problems with stabilizing clot,
● Disseminated intravascular coagulation hence once they start to form the
clot, bleeding happens again.

CONGENITAL BLEEDING DISORDERS

Hemophilia
an inherited bleeding disorder caused by deficiency of coagulation.

● Hemophilia A – Inherited deficiency of factor VIII (8); an X-linked recessive disorder. It is protected
from proteolysis in the circulation by binding to vWF

● Hemophilia B – Inherited deficiency of factor IX (9); also called Christmas Disease; an X-linked
recessive disorder.

● Hemophilia C – Inherited deficiency of factor XI (11); also called Rosenthal Syndrome; an

autosomal recessive disorder. Rarely, heterozygotes may have bleeding (ie, autosomal dominant
transmission, due to heterodimer binding). especially common in Ashkenazi Jews (ie, Jews from
Eastern Europe).

It’s characterized based on the residual or baseline factor activity level (also referred to as "factor
level"); expressed as a % of normal or in IU/mL.

Factor levels typically correlate with the degree of bleeding Symptoms. (Important)

• Severe Hemophilia – defined as <1 % factor activity (<0.01 IU/mL).

• Moderate Hemophilia – defined as a factor activity level ≥1 % of normal and <5 % of normal ( ≥0.01
- <0.05 IU/mL).
• Mild Hemophilia – defined as a factor activity level ≥5 % of normal and <40 % of normal (≥0.05 -
<0.40 IU/mL).
Congenital >> genetic mutation in F8 & F9 located on the long arm of X chromosome.
▪ Observed commonly in males due to their hemizygous state
▪ Rarely in females due to (Heterozygous females as result from nonrandom X
chromosome inactivation, skewed Lyonization, or the presence of other genetic
abnormalities (Turner Syndrome or X autosomal translocations).

Acquired >> development of autoantibodies most commonly directed against FVIII – ass. with
pregnancy, malignancy, advanced age.

Clinically >> hematomas, hemarthroses, bruising, bleeding (mucosal, GI, GU)

Dx >> aPTT will be prolonged, Factor level will be low, Mixing study (corrected), Normal VWF &
PT (the most accurate test is a specific assay for factor VIII or IX)
Rx >> Replacement of the deficient coagulation Factor (recombinant or plasma derived) + Adjunctive
therapy (Desmopressin (DDAVP levels of vwf will increase with this drug), Antifibrinolytic agents
(Tranexamic Acid, Aminocaproic Acid), rFVIIa (with inhibitors)

According to the severity of hemophilia the treatment will differ:

- Sever: Prophylaxis is needed
- Mild: Give treatment if the pt bleeds, no need for prophylaxis

Von Willebrand Disease

The most common bleeding disorder.

Defect of Von Willebrand Factor:

● Quantitative (type 1 & 3)
● Qualitative (type 2)
Autosomal dominant (Important in MCQ)
The Normal function of VWF:
● Mediate platelet adhesion
● Stabilize factor VIII in circulation
● Localize factor VIII to site of vessel injury
Platelet aggregometry: testing for platelet dysfunction

To distinguish you need VW antigen

activity if its diminished with
factor 8 diagnostic

To confirm test for platelet ristocetin

activity

In case of VWF disease all will be

normal except ristocetin

● control ● thrombasthenia
Von Willebrand Disease
Congenital >> autosomal dominant (most types), recessive (rarely)

Acquired >> rare, caused by autoantibodies against vWF & immune complex formation,
vWF binding to cancer cells, Congenital Heart Disease, Aortic Stenosis, Angiodysplasia.
Rx (of the underlying disorder)

Dx >> normal aPTT in (Type 1 & 2), prolonged aPTT in (Type 2N, 2B, & 3), vWF:Ag,
vWF:RCo, vWF multimers (to differentiate subtypes), FVIII assay (low in 2N & 3), Plt
(low in 2M)

Rx >> Replacement of exogenous vWF concentrate, Desmopressin (DDAVP intranasal)

Antifibrinolytic agents (Tranexamic Acid, Aminocaproic Acid), Conjugated Estrogens &
oral contraceptive Agents (for menorrhagia)
(best initial therapy is desmopressin if there is no response use factor VIII replacement
or vWF concentrate)

Comparison between haemophilia and vWD

Hemophilia A Factor IX deficiency Von Willebrand
disease

inheritance sex-linked sex-linked Dominant

(incomplete)

Main sites of Muscle,joints,post-tra Muscle,joints,post-tra Mucous membranes,

hemorrhage uma or postoperative uma or postoperative skin cuts,
post-trauma or
postoperative

Platelet count Normal Normal Normal

Bleeding time Normal Normal prolonged

Prothrombin time Normal Normal Normal

Partial Prolonged Prolonged Prolonged or normal

thromboplastin time

Factor VIII low Normal May be moderately

reduced

Factor IX Normal low Normal

vWF Normal Normal low

Ristocetin-induced Normal Normal Impaired

platelet aggregation
Platelets Disorders
PLATELET COUNT

● 100,000 - 400,000 CELLS/MM3 (NORMAL)

● < 100,000 (Thrombocytopenia)
○ 50,000 - 100,000 (Mild Thrombocytopenia) (No need to give
platelets, just follow up)
○ < 50,000 (Severe Thrombocytopenia) (Need intervention)

Plt Disorders (Quantitative)

Causes of Thrombocytopenia

IMP

Portal HTN Cause back pressure on the spleen and

increase spleen size, this will lead to decrease in
All the cells including platelets so the pt if he
develop esophageal varices on top of
thrombocytopenia it will lend to severe bleeding

This is the extrahepatic manifestation of Hepatitis:

- one of them is thrombocytopenia
- the other is EVAN Syndrome

Evan syndrome:
- Autoimmune hemolytic cement
- Autoimmune thrombocytopenia
Approach to Thrombocytopenia

Immune Thrombocytopenic Purpura (ITP)

Primary : isolated thrombocytopenia due to immune Plt destruction & reduce production (auto
AB to megakaryocytes)
Secondary : a/w disease/drug exposure 🖝 Viral (HIV, HCV, HBV, EBV, CMV, Parvovirus), SLE,
APLS, H. Pylori Infection, Chronic Lymphocytic Leukemia (CLL), Hodgkin Lymphoma, AIHA

Dx >> Dx of exclusion, no robust clinical or Lab parameters, Typically CBC (Isolated 🖝 PLT <
100.000), 10% have ITP + AIHA (Evans Syndrome), PBS (Large Plts), Anti-Plt AB (not useful)

Clinically >> insidious onset of mucocutaneous bleed, M:F (3:1)

Rx >> rarely indicated if PLT > 50.000 unless bleeding, trauma/surgery, anticoag, comorbidities
Steroids, IVIG, Splenectomy, TPO agonists (Romiplostim, Eltrombopag)
 Immune Thrombocytopenic Purpura (ITP) Treatment
Very Important

Disseminated Intravascular Coagulation (DIC)

Etiology : Trauma, shock, infection, malignancy (esp APML*), Obstetric complications.
* IMP in MCQs (acute promyelocytic leukemia)
Pathogenesis :
massive activation of coagulation that overwhelms control mechanisms 🖝 thrombosis
Acute consumption of coagulation factors & Plts 🖝 bleeding

Dx >> Prolonged PT and aPTT, decreased fibrinogen, low plt, high LDH, low haptoglobin

Rx >> treat underlying process, FFP, Cryoprecipitate (Goal Fibrinogen > 100 mg/dL), PLT Tx

Q/ Which type of leukemia is common to have DIC?

A/ APML
 Plt Disorders (Qualitative )
ACQUIRED PLT FUNCTIONAL DISORDERS

1. Liver Disease
2. Cardiopulmonary Bypass
3. Uremia (CKD)
4. Dysproteinemia ( Multiple Myeloma or Waldenstrom Macroglobulinemia )
5. Myeloproliferative Disorders (MPDs)
6. Diabetes Mellitus
7. Acquired Glanzmann thrombasthenia

INHERITED DISORDERS OF PLT FUNCTION

1. Giant platelet disorders includes Plt GP abnormalities (eg, Bernard-Soulier Syndrome,

Deficiency of Platelet Alpha granules (eg, Gray Platelet Syndrome), Deficiency
May-Hegglin Anomaly (which also involves the presence of abnormal neutrophil
inclusions (ie, Döhle-like bodies)), & some kindreds with type 2B vWD (Montreal Plt
Syndrome)
2. Wiskott-Aldrich syndrome
3. Storage Pool Disorders such as Hermansky Pudlak Syndrome (HPS) (Hx of sore
throat+Purpura+Arthritis+Abdominal Pain+Nephropathy) (Deficiency of Dense
Granules)
4. Glanzmann thrombasthenia (aggregate in response to ristocetin)
5. Platelet release disorders
6. Glycoprotein VI defects
7. Sticky platelet syndrome
8. Congenital Deficiency of the ADP receptor P2Y12
9. Scott syndrome
Approach to Pt with Potential Bleeding
Two important points:
I. Detailed Pt & Family Medical History (Crucial & Vital regardless of the prior Lab testing)
II. Laboratory Testing

I. Detailed Pt & Family Medical History (Crucial & Vital regardless of the prior Lab testing)
establish likelihood of a bleeding disorder
guide laboratory Testing

• Early in the newborn period (circumcision)

• After hemostatic Challenges ( Delivery, injury, trauma, surgery, invasive dental procedure,
menstruation )
• Frequency & pattern
• Duration
o Symptoms onset ( congenital vs. acquired )
o time required for cessation

• Sites of bleeding (specific or multiple) (Very important)

Mucocutaneous Bleeding Deep Tissue Bleeding

• Easy bruising • Joints (Hemarthrosis)
• Epistaxis • Muscles
• Menorrhagia • Central Nervous
System (intracerebral hemorrhage)

Secondary Hemostasis
Primary Hemostasis
Defects
Defects
( Clotting Factors
( PLT or vW Factor )
Deficiencies )

• Current use of medications or herbal supplements

• Use of Bleeding Assessment Tools (differentiate bleeding phenotypes, require validation by
prospective studies)
 Drugs Used for Clotting Disorders
Generic Name Trade Name Half Life

Dabigatran Pradaxa 12 – 28 hr

Direct Thrombin Inhibitors Argatroban Acova 39 – 51 min

Lepirudin Refludan 1.3 hr

Bivalirudin Angiomax 25 – 57 min

Unfractionated Heparin …………………

Anticoagulants

(UFH) ………..

LMWH - Enoxaparin Clexan 4.5 – 7 hr

Indirect Thrombin Inhibitors LMWH - Tinzaparin Innohep 3 – 4 hr
-aprin
LMWH - Deltaparin

Fondaparinux Arixtra 17 – 21 hr

Vitamin K epoxide reductase

Inhibitor Warfarin Coumadin 7 – 11 hr

Rivaroxaban Xarelto 5 – 13 hr

Direct Xa Inhibitors Apixaban Eliquis 5 – 13 hr

-xaban
Endoxaban Savaysa 10 – 14 hr

Generic Name Trade Name Half Life

Aspirin ………………… 24 – 72 hr
Prostaglandin/COX Inhibitors ..………

Abciximab Reopro 72 hr
Antiplatelets

Eptifibatide Integrilin 4 hr
Glycoprotein IIb/IIIa
Inhibitors Tirofiban Aggrastat 4 hr

Clopidogrel Plavix 6 hr

Cangrelor Kengreal 3 – 6 min

P2Y₁₂ ADP Inhibitors
Prasugrel Effient 7 – 15 hr

Ticlopidine Ticlid 13 hr

Ticagrelor Brilinta 7- 9 hr
Thrombolytics Drugs Used for Clotting Disorders

Plasminogen
Activators
Tissue Alteplase
Plasminogen
Activators Reteplase
(t-PA) Tenecteplase

Streptokinase (SK)

Urikinase (UK)
 II. Laboratory Testing

Screening Tests
I. CBC (Platelet count)
II. Prothrombin Time (PT) >> measures F VII, X, V, II, I - (N Time 10-14 secs)
III. International Nmalized Ratio (INR) >> the ratio of a pt's PT to a normal (control) sample, raised
to the power of the ISI value for the control sample used.
IV. Activated Partial Thromboplastin Time (aPTT or PTT) >> measures F XII, XI, IX, VIII, X, V, II,
I - (N Time 30 – 40 secs)
V. Thrombin (Clotting) Time (TT) >> sensitive to deficiency of Fibrinogen or inhibition of thrombin
- (N Time 14 – 16 secs)
VI. Bleeding Time >> (3-8 secs) (not sensitive – not specific )

▪ Screening tests (not sensitive to all abnormalities ass. w a bleeding disorder)

Causes of Prolonged Coagulation Profile

Important MCQs Qs

Three patterns:
- Extrinsic pathway
- Intrinsic pathway
- Common Pathway (both tests
prolonged)
Specialized Tests
Mixing Study (one to one mix of Pt’s plasma & known normal standard plasma, only if PT of aPTT
prolonged)

● Corrected 🖝 clotting factor deficiency (risk of bleed)

● Not corrected 🖝 inhibitors (directed against specific factor or global inhibitors “ Lupus
Inhibitor, risk of thrombosis “)
1. PLT Function Assay (PFA - 100): assess PLT function
a. Specificity 🖝 90 % for severe PLT dysfunction of vWD (vWF plasma levels < 25%)
b. Sensitivity 🖝 24 – 41 % (low) in mild PLT secretion defect or Storage Pool Disease 🖝🖝
( not screening tool )
2. PLT Aggregation Tests: (5 external aggregating factors; ADP, Collagen, Ristocetin, Arachidonic
Acid, Adrenaline)
3. Von Willebrand Factor ( Antigen & Activity )
4. Factor XIII assay (F XIII Deficiency >> normal PT & PTT)
5. Human Plasminogen Activator Inhibitor (PAI-1)
6. Alpha 2 AntiPlasmin Inhibitor (α2 AP)
Take Home Message
Although screening tests are used widely to identify hemostatic abnormalities associated with bleeding,
they are NOT perfect
The Clinical suspicion for a bleeding disorder is Critical to determine extent of the laboratory investigations

Recommended Books by the doctor

Essential Hematology (A. V. Hoffbrand, P. A. H. Moss)
Uptodate
Oxford Handbook of clinical hematology.

There are extra slides from the doctor that can be found on this link
 Summary
We recommend this approach when reading the question

,vancomycin
 Summary
Hemophilia

A B C (ashkenazi jews)
Christmas Disease Rosenthal Syndrome

8 9 11

X linked recessive autosomal recessive

Severity and conformation assessed by Factor Levels:

Severe less than 1%
Moderate 1-5%
Mild 5-40%

Von Willebrand Disease

Etiology Qual or Quan, Autosomal dominant (except type 3)

Clinical -Mostly asymptomatic

-Ecchymosis,Petechiae
-Other symptoms include epistaxis, gingival bleeding, menorrhagia , GI
bleeding, and excessive bleeding during surgical procedures.

Lab -aPTT :normal (in Type 1 & 2) and prolonged (in Type 2N, 2B, & 3)
-Factor 8 will be low in type 2N & 3
-Quantitative assessment by vWF antigen assay: ↓ factor levels
-Qualitative assessment by a ristocetin cofactor activity assay Failure of
aggregation with a ristocetin assay or a ristocetin cofactor level < 30 IU/dL is
considered definitive for vWD

Rx Recombinant von Willebrand factor (rVWF) concentrate,Desmopressin

Immune thrombocytopenia

Clinical -Antecedent Viral infection

-Asymptomatic petechiae and ecchymosis
-Nasal,GI,GU bleed

Lab Diagnosis of exclusion

-Isolated thrombocytopenia
-Peripheral smear: megakaryocyte

Rx if PLT > 50.000 and no bleeding: observe

Other than that:
1st -Steroids, IVIG
2nd -Splenectomy
Refractory- TPO agonists (Romiplostim, Eltrombopag)
 DIC

Etiology Sepsis (most common),Trauma,malignancy(APML) ,Obstetric complications

Clinical -Bleeding + thrombosis

Lab - ↑PT, ↑aPTT, ↓ Fibrinogen (may be N b/c acute phase)

-+ve D-Dimer/FDP
-↓ PLT
-+ve Schistocytes, ↑ LDH, ↓ Haptoglobin

Rx treat underlying process, FFP, Cryoprecipitate (Goal Fibrinogen > 100 mg/dL),
PLT Tx

Questions

A. Low platelets
B. Prolonged Partial thromboplastin time
C. Prolonged Prothrombin time
D. Elevated ESR
E. Synovial fluid Leukocytosis
Answer B

A. Argatroban
B. Tranexamic acid
C. Protein C concentrate
D. Hyperbaric oxygen
Answer C
 A. Vitamin K
B. Plasma exchange
C. Intravenous Immunoglobulins
D. Desmopressin
E. Factor 8 Substitution
Answer D

A. Prolonged aPTT
B. Prolonged PT
C. Decreased level of vW Factor
D. High TSH
Answer is D (not just because it's all heavy menstrual periods are Bleeding disorder be careful in the exam)