In this article, we will review bleeding disorders caused by vessel wall abnormalities, platelet functional disorders, immune thrombocytopenic purpura, and thrombotic microangiopathies. These disorders share two common features – the bleeding disorder is not caused by an abnormality in the clotting factors and they present with bleeding without an effect on the international normalized ratio (INR).
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Vasculitis

Image : “Vasculitis” by James Heilman, MD. License: CC BY-SA 3.0


Classification of bleeding disorders

They can be classified into:

Disorders of the vessel wall

  1. Hereditary forms such as hereditary hemorrhagic telangiectasia and ehler-danlos syndrome.
  2. Acquired forms such as vitamin c deficiency, amyloidosis and Henoch schonlein purpura.

Disorders of clotting factor function

  1. Hereditary forms such as hemophilias, von Willebrand disease and dysfibrinogenemia.
  2. Acquired forms such as vitamin K deficiency and disseminated intravascular coagulopathy (DIC)

Disorders of platelet function

  1. Disorders due to reduced bone marrow function/ platelet production such as folate and B12 deficiency.
  2. Disorders of increased platelet consumption/platelet numbers such as DIC and idiopathic thrombocytopenic purpura.
  3. Disorders due to platelet function such as platelet adhesion disorders.
  4. Bleeding Disorders Due to Vascular Abnormalities

Definition and Overview

Defects in the blood vessels might cause a vascular bleeding disorder. Patients develop petechiae, purpura, and bruising. Bleeding disorders due to vascular abnormalities rarely cause serious blood loss, except for hereditary hemorrhagic telangiectasia. The coagulation profile in bleeding disorders due to vascular abnormalities is normal. The diagnosis is usually a clinical one.

Gardner-Diamond Syndrome

This is a rare autoerythrocyte sensitization disorder that affects mainly women. Patients develop local pain followed by unexplained painful ecchymoses on the extremities. There might be a history of trauma, however, the ecchymoses typically occur distant from the site of trauma. Ecchymoses never occur on the back of the patient.

This syndrome is seen in women with the psychiatric disease. The diagnosis is a clinical one and psychiatric treatment usually solves the problem. The pathogenesis and mechanism of the disorder are not known.

Dysproteinemias and Vascular Purpura

Conditions characterized by abnormal protein content in the blood and immune or protein deposition in the blood vessel wall are:

  • Amyloidosis
  • Cryoglobulinemia
  • Hypergammaglobulinemic purpura
  • Hyperviscosity syndrome

The blood vessels can become fragile and start leaking blood. Patients present with purpura and the lesions are typically small in size (< 2 mm). Large lesions such as ecchymoses or bruises might be also seen in these patients.

The diagnosis of amyloidosis can be confirmed with a biopsy. Cryoglobulins can be detected by laboratory testing. Patients with cryoglobulinemia typically have hepatitis C. Patients with hypergammaglobulinemic purpura have a polyclonal increase in IgG on their laboratory testing. Finally, patients with hyperviscosity syndrome have macroglobulinemia (elevated levels of IgA and IgG).

Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)

This is a hereditary disorder that is transmitted in an autosomal dominant fashion. There is a mutation in the receptor for transforming growth factor beta 1 and transforming growth factor beta 3 resulting into abnormal vessel formation in the skin, mucus membranes and organs such as the lungs liver and the brain.

The diagnosis is based on three main steps:

 Step 1 A careful history and physical evaluation.
 Step 2 Endoscopy or angiography to confirm gastrointestinal telangiectatic lesions for example.
 Step 3 Genetic testing to confirm the diagnosis and demonstrate a mutation in one of the previously mentioned genes.

The treatment of hereditary hemorrhagic telangiectasia can be summarized in the following points:

Causes Treatment
Nasal and gastrointestinal telangiectasias Significant hemorrhage Aggressively whenever bleeding
Vascular malformations in the brain Stroke and bleed Laser ablation, embolization, or surgical resection
Bleeding disorder Chronic blood loss Parenteral iron supplements

Surgical approaches to treat vascular malformations such as cerebral AVMs are also used.

Bleeding Disorders Due to Functional Platelet Abnormalities

Definition and Overview

Bleeding disorders due to functional platelet abnormalities might be hereditary or acquired.

The disorders of platelet function can be further classified into:

  • Disorders of platelet adhesion
  • Disorders of platelet secretion
  • Disorders of platelet aggregation
  • Disorders of platelet procoagulant activity
  • Combined abnormalities of platelet function and number

As it might be evident, for a platelet to be considered as normal functionally, it has to adhere to other platelets, secrete certain proteins for the activation of the clotting cascade and recruitment of more platelets and other cells, aggregate to other platelets, and have procoagulant activity. Moreover, the number of platelets available in the bloodstream need to be appropriate for bleeding to not occur.

Acquired platelet functional abnormalities are caused by aspirin, antiplatelet therapy, or the use of non-steroidal anti-inflammatory drugs.

Disorders of Platelet Adhesion

Megakaryocytes

Image : “Two megakaryoctes are visible in this slide of bone marrow” by Wbensmith. License: CC BY-SA 3.0

Bernard-Soulier syndrome is a rare disorder of platelet adhesion that is characterized by a deficiency of glycoprotein Ib/IX. This protein is found on the surface of the platelet and is responsible for platelet sticking and clumping to each other. Children with this disorder present with bruises, frequent nosebleeds, and bleeding from the mouth and gums. The coagulation profile is normal; however, the bleeding time is prolonged. The number of platelets might be low. On a blood smear, the platelets appear to be enlarged and they do not clump to each other in response to ristocetin.

Disorders of Platelet Secretion

The disorders of platelet secretion include alpha-granule deficiency, dense granule deficiency, and abnormal granule secretory mechanism.

Patients with a platelet secretion abnormality have:

  • Impaired platelet adhesion
  • Aggregation
  • Repair of blood vessels after injury

Disorders of Platelet Aggregation

Glanzmann thrombasthenia

The disease arises from abnormal GP IIb and IIIa which are required for proper platelet adhesion. The platelets only adhere to ristocetin. The disease can be classified into a severe form which has no glycoproteins detected or the mild form with reduced levels of glycoproteins in circulation.

The rare disorder Glanzmann Thrombasthenia presents with impaired platelet aggregation. Patients with this disorder might present with life-threatening bleeding. Platelets fail to plug to the site of an injury. There is a deficiency in the glycoprotein IIb/IIIa.

Combined Abnormalities of Platelets’ Number and Function

Some rare hereditary disorders affect platelets’ function and number. They include:

  • May-Hegglin anomaly
  • Alport syndrome
  • Wiskott-Aldrich Syndrome
The main cause of bleeding in these disorders is related to thrombocytopenia, not platelet dysfunction.

Immune Thrombocytopenic Purpura

Immune thrombocytopenic purpura (ITP) is a heterogeneous disease that is characterized by increased platelet clearance and insufficient platelet production. Tissue macrophages are responsible for platelet destruction in ITP. The process of destruction occurs in the spleen.

The destruction of platelets in ITP appears to be facilitated by the presence of IgG immunoglobulins, hence the term “immune”. Infection with hepatitis C, human immunodeficiency virus, or Helicobacter pylori might contribute to the production of these antibodies. The management of ITP revolves around corticosteroids, mainly prednisolone. After the cessation of prednisolone, some patients with ITP might develop cytopenias.

Patients with ITP who do not respond to prednisolone should receive one of the following treatments as second-line therapy:

  • Ciclosporin
  • Cyclophosphamide
  • Oral high-dose dexamethasone
  • Parenteral methylprednisolone
  • Danazol
  • High-dose intravenous immunoglobulin

Romiplostim and eltrombopag are TPO receptor agonists. They stimulate the production of platelets from the bone marrow and are both licensed for the treatment of ITP. If all of the above failed in treating thrombocytopenia, splenectomy might be considered.

Thrombotic Microangiopathies

These disorders present with microangiopathic hemolytic anemia, thrombocytopenia, and end-organ injury. The pathogenesis of thrombotic microangiopathies (TMA) includes vascular damage, arteriolar and capillary thrombosis, and endothelial cell abnormalities.

The following table summarizes the most common TMA syndromes, their characteristics, and management:

Name Etiology Clinical Features Treatment
Complement mediated TMA Mutations in CFH, C3, CD46 or other complement genes Occurs in children. Acute kidney injury is common. Plasma infusion or exchange.

Anti-complement therapy.

ADAMTS13 deficiency mediated TMA ADAMTS13 mutations Occurs in children. Presents with ischemic organ injury. Acute kidney injury is rare. Plasma infusion.
Coagulation mediated TMA DGKE, PLG, or THBD mutations Occurs in infants. Presents with acute kidney injury. Plasma infusion.
Acquired Thrombotic Thrombocytopenic Purpura (TTP) Autoantibody inhibition of ADAMTS13 Uncommon in children. Presents with ischemic organ injury. Kidney injury is rare. Plasma exchange and immunosuppressive therapy.
Shiga toxin-mediated TMA Enteric infection with Shiga toxin-producing strains of Escherichia coli or Shigella dysenteriae Common in young children. Presents with acute kidney injury. Outbreaks are common. Supportive care is needed.
Drug-mediated TMA:

Immune reaction

OR

Dose-related reaction

Immune reaction example: quinines.

Dose-related reaction involves the inhibition of vascular endothelial growth factor.

Sudden onset of symptoms with acute kidney injury.

OR

Gradual onset of renal failure over weeks to months.

Removal of drug and supportive care.
Complement-mediated TMA Antibody inhibition of complement factor H. Acute kidney injury. Seen in children and adults. Plasma exchange, immunosuppression, or anticomplement therapy.
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