This document discusses various bleeding disorders including hereditary haemorrhagic telangiectasia, scurvy, platelet function disorders, thrombocytopenia, haemophilia A, and coagulation disorders. It provides details on the causes, clinical presentations, diagnostic criteria, management, and treatment options for each condition. A case example is also included of a woman presenting with recurrent epistaxis and hematemesis who was diagnosed with hereditary haemorrhagic telangiectasia based on her family history and endoscopy/imaging findings showing telangiectasia and arteriovenous shunting.

1. Dr Abdirahman Abib, MD Family Medicine
BLEEDING DISORDERS

2. BLEEDING DISORDERS
Disorders of primary haemostasis
1. Vessel wall abnormalities:
 Hereditary haemorrhagic
telangiectasia
 Scurvy
2. Platelet function disorders:
 congenital or acquired
3. Thrombocytopenia:
 Idiopathic thrombocytopenic
purpura
 Haemophilia A
 Haemophilia B (Christmas
disease)
 Von Willebrand disease
 Acquired bleeding disorders

3. case
 A 44-year-old woman came with complaints of recurrent episodes
of hematemesis and epistaxis.
 Patient had a family history of similar complaints.
 Patient underwent esophagogastroduodenoscopy (EGD), which
revealed telangiectasia in the stomach.
 Imaging of the abdomen showed features suggestive of
arteriovenous shunting.

4. Hereditary haemorrhagic telangiectasia
 Hereditary haemorrhagic
telangiectasia (HHT) is a
dominantly inherited condition
caused by mutations in the genes
encoding endoglin and activin
receptor-like kinase, which are
endothelial cell receptors for
transforming growth factor-beta
(TGF-β), a potent angiogenic
cytokine.

5.  Diagnosis is based on the presence of at least three of the four following
symptoms: spontaneous epistaxis, cutaneous telangiectases,
arteriovenous malformations in internal organs, and positive familial
history.
 The main complications are severe anemia, portal and pulmonary
hypertension, hypoxemia, brain abscesses, and stroke.
 Telangiectasia and small aneurysms are found on the fingertips, face
tongue, and in the nasal passages, lung and gastrointestinal tract.
 A significant proportion of these patients develop larger pulmonary
arteriovenous malformations (PAVMs) that cause arterial hypoxaemia
right-to-left shunt.

6.  Patients present either with
recurrent bleeds, particularly
epistaxis, or with iron deficiency due
to occult gastrointestinal bleeding.
 Treatment can be difficult because
of the multiple bleeding points but
regular iron therapy often allows the
marrow to compensate for blood
loss.

7. Scurvy
 Vitamin C deficiency affects the normal
synthesis of collagen and results in a
bleeding disorder characterised by
perifollicular and petechial haemorrhage,
bruising and subperiosteal bleeding.
 The key to diagnosis is the dietary history.
 Tx vitamin c 800mg to 100mg day for a
week then 400mg daily for around 3
month. In this example, the perifollicular hyperkeratotic
papules are quite prominent, with surrounding
hemorrhage. These lesions have been
misinterpreted as "palpable purpura," leading to the
mistaken clinical diagnosis of vasculitis.
Perifollicular abnormalities
in scurvy

8. Platelet function disorders
 Bleeding may result from thrombocytopenia or from congenital or
acquired abnormalities of platelet function.
 The most common acquired disorders are iatrogenic, resulting from the
use of aspirin, clopidogrel.
 Inherited platelet function abnormalities are relatively rare.
 Congenital abnormalities may be due to deficiency of the membrane
glycoproteins, e.g. Glanzmann’s thrombasthenia (IIb/IIIa) or
Bernard–Soulier disease (Ib), or due to the presence of defective
platelet granules, e.g. a deficiency of dense (delta) granules.

9. Thrombocytopenia
 Thrombocytopenia occurs in many disease processes.

10. Thrombocytopenia as a result of drugs or toxins
 Bone marrow suppression
 Predictable (dose-related) ionizing radiation, cytotoxic drugs,
ethanol.
 Antimicrobials (pencillins, sulphonamides, trimethoprim, rifampicin )
 Diuretics (acetazolamide, chlorathiazides, frusemide )
 Anticonvulsants (dizepam, sodium valproate, carbamazepine )
 Antidiabetics (chlorpropamide, tolbutamide )
 Analgesics, anti-inflammatory drugs, gold salts

11. Idiopathic thrombocytopenic purpura
 Idiopathic thrombocytopenic purpura (ITP) is mediated by
autoantibodies, most often directed against the platelet membrane
glycoprotein IIb/IIIa, which sensitise the platelet, resulting in premature
removal from the circulation by cells of the reticulo-endothelial system.
 It is not a single disorder; some cases occur in isolation while others
are associated with underlying immune dysregulation in conditions such
as connective tissue diseases, HIV infection, B cell malignancies,
pregnancy and certain drug therapies.
 However, the clinical presentation and pathogenesis are similar,
whatever the cause of ITP.

12. Clinical features and investigations
 The presentation depends on the degree of thrombocytopenia.
 Spontaneous bleeding typically occurs only when the platelet count is
below 20 × 10^9/L.
 At higher counts, the patient may complain of easy bruising or
sometimes epistaxis or menorrhagia.
 Many cases with counts of more than 50 × 10^9/L are discovered by
chance.

13.  In adults, ITP more commonly affects females and may have an
insidious onset.
 Unlike ITP in children, it is unusual for there to be a history of a
preceding viral infection.
 Symptoms or signs of a connective tissue disease may be
apparent at presentation or emerge several years later.
 Patients aged over 65 years should have a bone marrow
examination to look for an accompanying B cell malignancy and
appropriate autoantibody testing performed if a diagnosis of
connective tissue disease is likely.

14. Management
 Many patients with stable compensated ITP and a platelet
count of more than 30 × 10^9/L do not require treatment to
raise the platelet count, except at times of increased
bleeding risk, such as surgery and biopsy.
 First-line therapy for patients with spontaneous bleeding is
with prednisolone 1 mg/kg daily to suppress antibody
production and inhibit phagocytosis of sensitized platelets by
reticuloendothelial cells.

15.  Administration of intravenous immunoglobulin (IVIg) can raise the
platelet count by blocking antibody receptors on reticuloendothelial
cells, and is combined with corticosteroid therapy if there is severe
haemostatic failure or a slow response to steroids alone.
 Persistent or potentially lifethreatening bleeding should be treated with
platelet transfusion in addition to the other therapies.
 The condition may become chronic, with remissions and relapses.
 Relapses should be treated by reintroducing corticosteroids.
 If a patient has two relapses, or primary refractory disease, splenectomy
is considered.

16. Heparin-Induced Thrombocytopenia
 Can occur with use of any amount of heparin.
 Mostly occurs with unfractionated heparin.
 Low–molecular-weight heparin (LMWH) has a much lower risk of
HIT.
 Drop in platelets a few days after heparin administration. Platelets
aggregate (“clump”) leading to venous thrombosis (DVT, PE )
 Decrease in platelet count by 50% suggests HIT.
 Diagnostic tests: antiplatelet factor IV antibody or serotonin release
assay
 Treatment: stop heparin. If anticoagulation is indicated (venous
thrombosis), give a thrombin inhibitor such as lepirudin.
 Avoid heparin in the future in any patient who has developed an
episode of HIT.

17. Coagulation disorders
 Coagulation factor deficiency may be congenital or acquired, and
may affect one or several of the coagulation factors.
 Inherited disorders are almost uniformly related to decreased synthesis,
as a result of mutation in the gene encoding a key protein in coagulation.
 Von Willebrand disease is the most common inherited bleeding
disorder.
 Haemophilia A and B are the most common single coagulation factor
deficiencies, but inherited deficiencies of all the other coagulation factors
are seen.
 Acquired disorders may be due to under-production (e.g. in liver
failure), increased consumption (e.g. in disseminated intravascular
coagulation) or inhibition of function (such as heparin therapy or
immune inhibitors of coagulation, e.g. acquired haemophilia A).

18. Haemophilia A
 Factor VIII deficiency resulting in haemophilia A affects 1/10 000
individuals.
 It is the most common congenital coagulation factor deficiency.
 Factor VIII is primarily synthesised by the liver and endothelial cells,
and has a half-life of about 12 hours.
 It is protected from proteolysis in the circulation by binding to von
Willebrand factor (vWF).

19. Clinical features
 The extent and patterns of bleeding are closely related to residual
factor VIII levels.
 Patients with severe haemophilia (< 1% of normal factor VIII levels)
present with spontaneous bleeding into skin, muscle and joints.
 Retroperitoneal and intracranial bleeding is also a feature.
 Babies with severe haemophilia have an increased risk of intracranial
haemorrhage and, although there is insufficient evidence to recommend
routine caesarean section for these births, it is appropriate to avoid
head trauma and to perform imaging of the newborn within the first 24
hours of life.

20.  Individuals with moderate and mild haemophilia (factor VIII levels 1–
40%) present with the same pattern of bleeding, but usually after
trauma or surgery, when bleeding is greater than would be expected
from the severity of the insult.
 The major morbidity of recurrent bleeding in severe haemophilia is
musculoskeletal.
 Bleeding is typically into large joints, especially knees, elbows, ankles
and hips.
 Muscle haematomas are also characteristic, most commonly in the calf
and psoas muscles.

21. Management
 In severe haemophilia A, bleeding episodes should be treated by
raising the factor VIII level, usually by intravenous infusion of factor
VIII concentrate.
 Factor VIII concentrates are freeze-dried and stable at 4°C and can
therefore be stored in domestic refrigerators, allowing patients to treat
themselves at home at the earliest indication of bleeding.
 Factor VIII concentrate prepared from blood donor plasma is now
screened for HBV, HCV and HIV, and undergoes two separate virus
inactivation processes during manufacture; these preparations have a
good safety record.

22.  The vasopressin receptor agonist DDAVP raises the vWF and factor
VIII levels by 3–4-fold, which is useful in arresting bleeding in patients
with mild or moderate haemophilia A.
 In addition to treatment ‘on demand’ for bleeding, factor VIII can be
administered 2 or 3 times per week as ‘prophylaxis’ to prevent bleeding
in severe haemophilia.
 This is most appropriate in children, but its widespread use is limited by
the high cost of factor VIII preparations.

23. Complications of coagulation factor
therapy
 Infections: HIV and hepatitis viruses HBV and HCV.
 Development of anti-factor VIII antibodies.

24. case
 Patient 5-month-old Caucasian male presented for evaluation of a
markedly elevated partial thromboplastin time (PTT) that was first
detected immediately following birth . the patient’s Factor IX level
was found to be markedly decreased.
 An inhibitor screen was performed at this time and was negative.
 Medical History: The patient was born without complications by
spontaneous vaginal delivery. The pregnancy was unremarkable.
The patient had not bled since birth. Family History The patient’s
mother was a symptomatic hemophilia B carrier with a Factor IX
level of 16%, and his maternal uncle had moderate hemophilia B
with a Factor IX level of 2%.
 Physical Exam Findings No signs of any bleeding.

26. Haemophilia B (Christmas disease)
 Aberrations of the factor IX gene, which is also present on the X
chromosome, result in a reduction of the plasma factor IX level, giving
rise to haemophilia B.
 This disorder is clinically indistinguishable from haemophilia A but is
less common.
 The frequency of bleeding episodes is related to the severity of the
deficiency of the plasma factor IX level.
 Treatment is with a factor IX concentrate, used in much the same way as
factor VIII for haemophilia A.
 Although factor IX concentrates shared the problems of virus transmission
seen with factor VIII, they do not commonly induce inhibitor antibodies
(< 1% patients).

27. Von Willebrand disease
 Von Willebrand disease is a common but usually mild bleeding disorder
caused by a quantitative (types 1 and 3) or qualitative (type 2)
deficiency of von Willebrand factor (vWF), a protein synthesised by
endothelial cells and megakaryocytes, which is involved in both platelet
function and coagulation.
 It normally forms a multimeric structure which is essential for its
interaction with subendothelial collagen and platelets
 Most patients with von Willebrand disease have a type 1 disorder,
characterised by a quantitative decrease in a normal functional protein.
 Patients with type 2 disorders inherit vWF molecules that are functionally
abnormal.
 The type of abnormality depends on the site of the mutation in the vWD
gene.

28. Clinical features
 Patients present with haemorrhagic manifestations similar to those in
individuals with reduced platelet function.
 Superficial bruising, epistaxis, menorrhagia and gastrointestinal
haemorrhage are common.
 Bleeding episodes are usually much less common than in severe
haemophilia and excessive haemorrhage may only be observed after
trauma or surgery.
 Within a single family, the disease has variable penetrance, so that some
members may have quite severe and frequent bleeds, whereas others
are relatively asymptomatic.

29. Investigations
 Combination of assays which include functional and antigenic measures of
vWF.
 Analysis for mutations in the vWF gene is informative in most cases.
 Managements:
 Many episodes of mild haemorrhage can be successfully treated by local
means or with DDAVP, which raises the vWF level, resulting in a
secondary increase in factor VIII.
 Tranexamic acid may be useful in mucosal bleeding.
 For more serious or persistent bleeds, haemostasis can be achieved with
selected factor VIII concentrates which contain considerable quantities
of vWF in addition to factor VIII.

30. Acquired bleeding disorders
 Liver disease and the tendency of bleeding : presentation
 Renal failure and the tendency of bleeding : presentation.

31. anticoagulant therapy
 The primary need for oral anticoagulant therapy is in the
prophylaxis against thrombosis in high-risk circumstances such as:
 chronic atrial fibrillation
 mechanical heart valve replacement,
 the continuing treatment of thrombophlebitis and pulmonary
thromboembolism.
 Postoperative use of anticoagulant therapy has become a common
event after orthopedic surgery to lessen the risk of venous
thrombosis

32.  Dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis)
are all approved for use in patients with atrial fibrillation and could
replace warfarin in some instances because the bleeding risk and
need for follow-up laboratory monitoring are reduced

34. Disseminated Intravascular Coagulation
(DIC):
 DIC is characterized by abnormal activation of the coagulation
sequence, leading to formation of microthrombi throughout the
microcirculation.
 causes consumption of platelets, fibrin, and coagulation factors.
 Fibrinolytic mechanisms are activated, leading to hemorrhage.
 Therefore, bleeding and thrombosis occur simultaneously.

35. Causes:
 Infection: most common cause, especially gram-negative sepsis.
 Obstetric complications: amniotic fluid emboli (often acute and
fatal); retained dead fetus (often chronic); abruptio placentae.
 Major tissue injury: trauma, major surgery, burns, fractures.
 Malignancy: acute promyelocytic leukemia e ,lungs, pancreas,
prostate, GI tract
 Shock, circulatory collapse
 Snake venom (rattlesnakes)

36. Pathogenesis:
 massive activation of coagulation that overwhelms control
mechanisms - thrombosis
 Acute consumption of coagulation factors &Plts
 bleeding Investigations and diagnosis:
 Elevation in both the PT and aPTT
 Low platelet count
 Elevated d-dimer and fibrin split products
 Decreased fibrinogen level (it has been consumed)

37. Treatment:
 Treat the underlying cause.
 If platelets are under 50,000/microleter and the patient has serious
bleeding, replace platelets as well as clotting factors by using FFP
(Fresh Frozen Plasma).
 Heparin has no definite benefit.
 Cryoprecipitate may be effective to replace fibrinogen levels if FFP
does not control bleeding.

38.  END